PYRIMIDINE-2,4,6-TRIONE METALLOPROTEINASE INHIBITORS

INHIBITEURS DE LA PYRIMIDINE-2,4,6-TRIONE METALLOPROTEINASE

English Abstract

The present invention relates to pyrimidine-2,4,6-trione metalloproteinase
inhibitors of the formula (I) wherein X, Y, A, B and R1 are as defined in the
specification, and to pharmaceutical compositions and methods of treating
inflammation, cancer and other disorders.

French Abstract

La présente invention concerne des inhibiteurs de la pyrimidine-2,4,6-trione métalloproteinase de formule (I), dans laquelle X, Y, A, B et R?1¿ sont définis comme dans la description, ainsi que des compositions pharmaceutiques et des méthodes de traitement d'inflammations, de cancers et autres troubles.

Claims

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CLAIMS

1. A compound of the formula
Image
wherein A is optionally substituted (C6-C10)aryl or (C1-C10)heteroaryl;
B is optionally substituted (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-
C10)heteroaryl,
(C1-C10)heterocyclic, (C6 C10)aryl-(C1-C4)alkyl, (C3-C8)cycloalkyl-(C1-
C4)alkyl,
(C1-C10)heteroaryl-(C1-C4)alkyl or (C1-C4)heterocyclic-(C1-C4)alkyl; wherein
each of the aforesaid
(C3-C8)cycloalkyl or (C1-C10)heterocyclic may optionally contain one or two
double bonds;

wherein A and B may be independently optionally substituted on any of the ring
carbon
atoms capable of forming an additional bond by one or two substituents
independently selected
from F, CI, Br, CN, OH, (C1-C4)alkyl, (C1-C4)pertluoroalkyl, (C1-
C4)perfluoroalkoxy, (C1-C4)alkoxy,
and (C3-C8)cycloalkyloxy;

X is selected from the group consisting of oxygen, >C=O, sulfur, >SO2, >S=O,
>NR10,
-CH2O-, -OCH2 , -CH2S-, -CH2(S=O)-, -CH2SO2, -SCH2, -SOCH2, -SO2CH2, -
[N(R10)]CH2,
-CH2[N(R10)]-, -[N(R10)]SO2 and -SO2[N(R10)]-;

Y is selected from the group consisting of a bond, oxygen, sulfur, >C=O, >SO2,
>S=O,
>NR12, -CH2, -CH2O-, -OCH2, -CH2S-, -CH2(S=O)-, -CH2SO2, -SCH2, -(S=O)CH2, -
SO2CH2,
-[N(R12)]CH2, -CH2[N(R12)]-, -CH2CH2-, -CH=CH-, -[N(R12)]-SO2- and -
SO2[N(R12)]-;

R1 is hydrogen, (R2)2n+1 -(C)n- or (C3-C8)cycloalkyl wherein said (C3-
C8)cycloalkyl may
also optionally be substituted by one to two substituents independently
selected from halo,
(C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)alkynyl, R3-, R3-O-, perfluoro(C1-
C4)alkoxy,

R3-(C1-C4)alkyl-O-, R3-(C=O)-O-, (R3)2N-(C=O)-O-, -NO2, (R3)2N-, R3-(C=O)-
(NR4)-,
R3-(SO2)-(NR4)-, R3O-(C=O)-(NR4)-, (R3)2-N-(C=O)-(NR4)-, R3-S-, R3-(S=O)-, R3-
(SO2)-.

(R3)2N-(SO2)-, -CN, R3-(C=O)-, R3-O-(C=O)- and (R3)2N-(C=O)-

n is an integer from one to ten;
each R2 is independently selected from the group consisting of halo, (C,-
C4)alkenyl,
(C1-C4)alkynyl, R3-, R3-O-, perfluoro(C1-C4)alkoxy, R3-(C=O)-O-, (R3)2N-(C=O)-
O-, -NO2, (R3)2N-,
R3-(SO2)-(NR4)-, (R3)2-N-(C=O)- R3-(C=O)-(NR4)-, R3-O-(C=O)-(NR4)-, (R3)2-N-
(C=O)-(NR4)-,
R3-S-, R3-(S=O)-, R3-(SO2)-, (R3)2N-(SO2)-, -CN, R3-O-(C=O)- and R3-(C=O)-;
wherein not more
than three of said R2 substituents may be other than hydrogen and any one
carbon atom of said
-(C)n- group can contain only one bond to a heteroatom; wherein a carbon atom
of any two R2



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groups may be taken together with the carbons to which they are attached to
form a four to ten
membered ring;

each R3 is independently selected from the group consisting of hydrogen, (C1-
C4)alkyl,
(C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
wherein each R3
may be optionally substituted on any carbon atom able to support an additional
substitutent,
by one to three substitutents per alkyl moiety or by one to three
substitutents per ring,
independently selected from the group consisting of halo, hydroxy, amino, -CN,
(C1-C4)alkyl,
(C1-C4)alkoxy, (C1-C4)alkyl-NH-, [(C1-C4)alkyl]2-N-, (C6-C10)aryl, (C3-
C8)cycloalkyl,
(C1-C10)heteroaryl and (C1-C10)heterocyclyl; wherein said (C3-C8)cycloalkyl
and
(C1-C10)heterocyclyl may also optionally be substituted by oxo; wherein said
(C3-C10)heteroaryl
and (C1-C10)heterocyclyl may optionally be substituted on any ring nitrogen
atom able to
support an additional substitutent by one to two substitutents per ring
independently selected
from the group consisting of (C1-C4)alkyl, (C1-C4)alkyl-(C=O)-, (C6-C10)aryl,
(C3-C8)cycloalkyl,
(C1-C10)heteroaryl and (C1-C10)heterocyclyl; ~

wherein said R3 group may optionally be taken together with an R4 group to
form a
three to eight membered ring; wherein two of said R4 groups may be taken
together to form a
three to eight membered ring;
R4 wherever it occurs is independently selected from hydrogen and (C1-
C4)alkyl;
G is R5- or R6-(CHR13)P ; wherein G is a substituent on any ring carbon atom
of B
capable of forming an additional bond and is oriented at a position other than
alpha to the point
of attachment of the B ring to Y;
p is an integer from one to six;

wherein R5 is selected from the group consisting of R7-, R11-O-, R7-(C1-
C4)alkyl-O-,
R8-(C=O)-O-, H2N(C=O)-O-, R8-NH(C=O)-O-, (R8)2N(C=O)-O-, R6-S-, R8-(S=O)-, R8-
(SO2)-,
H2N-(SO2)-, R8-NH-(SO2)-, (R8)2N-(SO2)-, formyl, R8-(C=O)-, HO-(C=O)-, R8-O-
(C=O)-,
H2N-(C=O)-, R8NH-(C=O)-, (R8)2N-(C=O)-, -NO2, NH2, R8-NH-, (R8)2N-, H(C=O)-
(NR9)-,
R8-(C=O)-(NR9)-, H2N-(C=O)-(NR9)-, R8NH-(C=O)-(NR9)-, (R8)2N-(C=O)-(NR9)-,
R8O-(C=O)-(NR9)-, R8-(C=O)-(NR9)-, R8-(SO2)-NH- and R8-(SO2)-(NR9)-;

R6 is selected from the group consisting of (C1-C4)alkenyl, (C1-C4)alkynyl,
R7, OH,
R8-O-, R8-(C1-C4)alkyl-O-, perfluoro(C1-C4)alkoxy, R8-(C=O)-O-, H2N(C=O)-O-,
R8-NH(C=O)-O-, (R8)2N(C=O)-O-, R8-S-, R8-(S=O)-, R8-(SO2)-, HEN-(SO2)-, R8-NH-
(SO2)-,
(R8)2N-(SO2)-, formyl, -CN, R8-(C=O)-, HO-(C=O)-, RB-O-(C=O)-, H2N-(C=O)-,
R8NH-(C=O)-,
(R8)2N-(C=O)-, -NO2, NH2, R8-NH-, (R8)2N-, H(C=O)-(NR9)-, R8-(C=O)-(NR9)-,
H2N-(C=O)-(NR9)-, R8NH-(C=O)-(NR9)-, (R8)2N-(C=O)-(NR9)-, R8O-(C=O)-(NR9)-,
R8-(SO2)-NH- and R8-(SO2)-(NR9)-;



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R7 is selected from the group consisting of (C6-C10)aryl, (C3-C8)cycloalkyl,
(C1-C10)heteroaryl and (C1-C10)heterocyclyl; wherein said (C6-C10)aryl, (C3-
C8)cycloalkyl,
(C1-C10)heteroaryl and (C1-C10)heterocyclyl moieties may be optionally
substituted on any of the
ring carbon atoms capable of forming an additional bond by one to three
substituents per ring
independently selected from F, CI, Br, CN, OH, (C1-C4)alkyl, (C1-
C4)perfluoroalkyl,
(C,-C4)perfluoroalkoxy, (C,-C4)alkoxy, amino, (C1-C4)alkyl-NH-, [(C1-
C4)alkyl]2-N- and
(C3-C8)cycloalkyloxy; wherein said (C3-C8)cycloalkyl and (C1-C10)heterocyclyl
moieties may
also optionally be substituted by oxo; wherein said (C1-C10)heteroaryl and (C1-
C10)heterocyclyl
moieties may optionally be substituted on any ring nitrogen atom able to
support an additional
substitutent by one to two substitutents per ring independently selected from
the group
consisting of (C1-C4)alkyl and (C1-C4)alkyl-(C=O)-;

R8 is selected from the group consisting of (C1-C4)alkyl, (C6-C10)aryl, (C3-
C8)cycloalkyl,
(C1-C10)heteroaryl and (C1-C10)heterocyclyl; wherein each R8 may be optionally
substituted on
any carbon atom able to support an additional substitutent, by one to three
substitutents per
alkyl moiety or by one to three substitutents per ring, independently selected
from the group
consisting of F, CI, Br, CN, OH, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-
C4)perfluoroalkoxy,
(C1-C4)alkoxy, and (C3-C8)cycloalkyloxy; wherein said (C3-C8)cycloalkyl and
(C1-C10)heterocyclyl may also optionally be substituted by oxo; wherein said
(C1-C10)heteroaryl
and (C1-C10)heterocyclyl may also optionally be substituted on any ring
nitrogen atom able to
support an additional substitutent by one to two substitutents per ring
independently selected
from the group consisting of (C1-C4)alkyl and (C1-C4)alkyl-(C=O)-; wherein two
of said R8 may
optionally be taken together with the heteroatom to which they are attached to
form a three to
eight membered ring;

R9 wherever it occurs is independently selected from hydrogen and (C1-
C4)alkyl;
wherein said R8 and R9 may optionally be taken together with the heteroatoms
to which they are
attached to form a three to eight membered ring;

R10 wherever it occurs is independently selected from hydrogen and (C1-
C4)alkyl;

R11 is selected from the group consisting of (C6-C10)aryl, (C1-C10)heteroaryl
and
(C1-C10)heterocyclyl; wherein said (C6-C10)aryl, (C1-C10)heteroaryl and (C1-
C10)heterocyclyl
moieties may be optionally substituted on any of the ring carbon atoms capable
of forming an
additional bond by one to three substituents per ring independently selected
from F, CI, Br, CN,
OH, (C1-C4)alkyl, (C1-C4)perfluoroalkyl, (C1-C4)perfluoroalkoxy, (C1-
C4)alkoxy, and
(C3-C8)cycloalkyloxy; wherein said (C1-C10)heterocyclyl may also optionally be
substituted by
oxo; wherein said (C1-C10)heteroaryl and (C1-C10)heterocyclyl may optionally
be substituted on
any ring nitrogen atom able to support an additional substitutent by one to
two substitutents



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per ring independently selected from the group consisting of (C1-C4)alkyl and
(C1-C4)alkyl-(C=O)-;

R12 wherever it occurs is independently selected from hydrogen and (C1-
C4)alkyl;

R13 is independently selected from hydrogen and (C1-C4)alkyl; wherein R13 may
optionally be taken together with R6 to form a four to 10 membered ring;
or a pharmaceutically acceptable salt thereof.

2. A compound according to any of the previous claims, wherein X is oxygen,
-OCH2 or -CH2O-.

3. A compound according to any of the previous claims, wherein Y is oxygen,
-OCH2 or -CH2O-.

4. A compound according to any of the previous claims, wherein A is optionally
substituted phenyl.

5. A compound according to any of the previous claims, wherein B is optionally
substituted phenyl (C1-C10)heteroaryl.

6. A compound according to any of the previous claims, wherein G is R5-.

7. A compound according to any of the previous claims, wherein R5- is R7,

wherein R7 is (C1-C10)heteroaryl.

8. A compound according to any of the previous claims, wherein R1 is (R2)2n+1-
(C)n- is an integer from one to ten;

at least one R2 is independently selected from the group consisting of R3-, R3-
O-,
(R3)2N-, R3-S-, R3-(S=O)-, R3-(SO2)-, R3-(SO2)-(NR4)-, R3-NH-(SO2)-, (R3)2N-
(SO2)-
R3-(C=O)-(NR4)-, R3-(C=O)-O-, R3-O-(C=O)- and R3-(C=O)-; and
each R3 is independently selected from the group consisting of hydrogen and
(C1-C4)alkyl; wherein each R3 (C1-C4)alkyl moiety may be optionally
substituted by one to
three substitutents independently selected from the group consisting of halo,
hydroxy, amino,
-CN, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl-NH-, [(C1-C4)alkyl]2-N- (C6-
C10)aryl,
(C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; wherein said
R3 group may
optionally be taken together with R4 to form a three to eight membered ring.

9. A compound according to claim 1, wherein said compound is selected from
the group consisting of:

5-(2-Ethoxy-ethyl)-5-[4-(4-thiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(1-methyl-1H-pyrazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;


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5-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

phenyl)-pentanenitrile;

5-(2-Ethoxy-ethyl)-5-{4-[4-(2-methyl-thiazol-4-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(1 H-pyrazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-[4-(4-oxazol-5-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione; and
5-(2-Ethoxy-ethyl)-5-[4-(4-pyrimidin-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition for the treatment of a condition selected
from the
group consisting of connective tissue disorders, inflammatory disorders,
immunology/allergy
disorders, infectious diseases, respiratory diseases, cardiovascular diseases,
eye diseases,
metabolic diseases, central nervous system (CNS) disorders, liver/kidney
diseases,
reproductive health disorders, gastric disorders, skin disorders and cancers
in a mammal,
including a human, comprising an amount of a compound according to any of the
previous
claims effective in such treatment and a pharmaceutically acceptable carrier.

11. A method for treating a condition selected from the group consisting of
connective tissue disorders, inflammatory disorders, immunology/allergy
disorders, infectious
diseases, respiratory diseases, cardiovascular diseases, eye diseases,
metabolic diseases,
central nervous system (CNS) disorders, liver/kidney diseases, reproductive
health disorders,
gastric disorders, skin disorders and cancers in a mammal, including a human,
comprising
administering to said mammal an amount of a compound according toany of the
previous claims,
effective in treating such a condition.

Description

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PYRIMIDINE-2.4.6-TRIONE METALLOPROTEINASE INHIBITORS
Background of the Invention
The present invention relates to pyrimidine-2,4,6-trione metalloproteinase
inhibitors, and
to pharmaceutical compositions and methods of treatment of inflammation,
cancer and other
disorders.
The compounds of the present invention are inhibitors of zinc
metalloendopeptidases,
especially those belonging to the class of matrix metalloproteinases (also
called MMP or
matrixin).
The MMP subfamily of enzymes, currently contains seventeen members (MMP-1,
MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-13, MMP-14,
MMP-15, MMP-16, MMP-17, MMP-18, MMP-19, MMP-20). The MMP's are most well known
for their role in regulating the turn-over of extracellular matrix proteins
and as such play
important roles in normal physiological processes such as reproduction,
development and
differentiation. In addition, the MMP's are expressed in many pathological
situations in which
abnormal connective tissue turnover is occurring. For example, MMP-13 an
enzyme with
potent activity at degrading type II collagen (the principal collagen in
cartilage), has been
demonstrated to be overexpressed in osteoarthritic cartilage (Mitchell, et
al., J. Clin. Invest.,
97, 761 (1996)). Other MMPs (MMP-2, MMP-3, MMP-8, MMP-9, MMP-12) are also
overexpressed in osteoarthritic cartilage and inhibition of some or all of
these MMP's is
expected to slow or block the accelerated loss of cartilage typical of joint
diseases such as
osteoarthritis or rheumatoid arthritis.
It is recognized that different combinations of MMP's ,are expressed in
different
pathological situations. As such, inhibitors with specific selectivities for
individual MMP's may
be preferred for individual diseases.
Matrix metalloproteinase inhibitors are well known in the literature.
Hydroxamic acid
MMP inhibitors are exemplified in European Patent Publication 606,046,
published July 13,
1994. Several pyrimidine-2,4,6 trione MMP inhibitors are referred to in PCT
publication WO
98/58925, published December 30, 1998. PCT publication WO 00/47565, published
August
17, 2000 refers to certain aryl substituted pyrimidine-2,4,6-trione MMP
inhibitors. United
States Non-provisional application 09/635156, filed August 9, 2000 (which
claims priority to
United States Provisional application 60/148547 filed August 12, 1999) refers
to heteroaryl
substituted pyrimidine-2,4,6 trione MMP inhibitors. United States Provisional
Application
entitled "Spiro-Pyrimidine-2,4,6-Trione Metalloproteinase Inhibitors", filed
October 26, 2000,
refers to certain 5-spiro pyrimidin-2,4,6-triones. Barbituric acids and
methods for their
preparation are well known in the art, see for example Goodman and Gilman's,
"The
Phamacological Basis of Therapeutics," 345-382 (Eighth Edition, McGraw Hill,
1990). Each of
SUBSTITUTE SHEET (RULE 26)


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the above referenced publications and applications is hereby incorporated by
reference in its
entirety
Summary of the Invention
The present invention relates to compounds of the formula:
O
HEN X-A-Y- B-G
I
O' 'N O
I
H
wherein A is optionally substituted (C6 C,°)aryl or (C2
C,°)heteroaryl;
B is optionally substituted (C6 C,°)aryl, (C3 C8)cycloalkyl, (C,-
C,o)heteroaryl, (C,
C,o)heterocyclic, (C6 C,°)aryl-(C,-C4)alkyl, (C3 C8)cycloalkyl-(C,-
C4)alkyl, (C,-C,°)heteroaryl-(C,
C4)alkyl or (C,-C,°)heterocyclic-(C,-C4)alkyl; wherein each of the
aforesaid (C3 Ce)cycloalkyl or
(C,-C,°)heterocyclic may optionally contain one or two double bonds;
wherein A and B may be independently optionally substituted on any of the ring
carbon
atoms capable of forming an additional bond by one or two substituents
independently selected
from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)pertluoroalkyl, (C,-
C4)pertluoroalkoxy, (C,-C4)alkoxy,
and (C3 CB)cycloalkyloxy;
X is selected from the group consisting of oxygen, >C=0, sulfur, >SOz, >S=0,
>NR'°,
-CH20-, -OCHZ , -CHzS-, -CHZ(S=O)-, -CHZSOZ , -SCHz , -SOCHZ , -SO2CH2 , -
[N(R'°)]CHZ ,
-CHZ[N(R'°)]-, -[N(R'°)]SOZ and -SOZ[N(R'°)]-;
Y is selected from the group consisting of a bond, oxygen, sulfur, >C=0, >S02,
>S=0,
>NR'~, -CHz , -CHzO-, -OCHz , -CHzS-, -CHZ(S=O)-, -CHzSOz , -SCHz , -(S=O)CHZ
, -SOzCHz , -
[N(R'z)]CHz , -CHZ[N(R'z)]-, -CHzCH2 , -CH=CH-, -[N(R'2)]-SOZ and -SOZ[N(R'2)]-
;
R' is hydrogen, (R2)2"+,-(C)~ or (C3 C8)cycloalkyl wherein said (C3
Ce)cycloalkyl may
also optionally be substituted by one to two substituents independently
selected from halo,
(C,-C4)alkyl, (C,-C4)alkenyl, (C,-C4)alkynyl, R3-, R3-O-, perfluoro(C,-
C4)alkoxy,
R3-(C,-Ca)alkyl-O-, R3-(C=O)-O-, (R3)zN-(C=O)-O-, -NOa, (R3)zN-, R3-(C=O)-
(NR4)-,
R3-(SOz)-(NR4)-, R30-(C=O)-(NR4)-, (R3)z-N-(C=O)-(NR4)-, R3-S-, R3-(S=O)-, R3-
(SOZ)-,
(R3)zN-(SOZ)-, -CN, R3-(C=O)-, R3-O-(C=O)- and (R3)zN-(C=O)-;
n is an integer from one to ten;
each RZ is independently selected from the group consisting of halo, R3-, (C,-
CQ)alkenyl,
(C,-C4)alkynyl, R3-O-, perfluoro(C,-C,)alkoxy, R3-(C=O)-O-, (R3)ZN-(C=O)-O-, -
NOZ, (R3)ZN-,
R3-(SOZ)-(NR4)-, R3-(C=O)-(NR4)-, R30-(C=O)-(NRd)-, (R3)z-N-(C=O)-(NR4)-. R3-S-
, R3-(S=O)-,
R3-(SOZ)-, (R3)ZN-(SOZ)-, -CN, R3-(C=O)-, R3-O-(C=O)- and (R3)zN-(C=O)-;
wherein not more
SUBSTITUTE SHEET (RULE 26)


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than three of said Ra substituents may be other than hydrogen and any one
carbon atom of said
-(C)~ group can contain only one bond to a heteroatom; wherein a carbon atom
of any two Rz
groups may be taken together with the carbon atoms to which the Rz groups are
attached to form
a four to ten membered ring;
each R3 is independently selected from the group consisting of hydrogen, (C,-
C4)alkyl,
(C6 C,o)aryl, (C3 Ce)cycloalkyl, (C,-C,o)heteroaryl and (C,-C,o)heterocyclyl;
wherein each R3
may be optionally substituted on any carbon atom able to support an additional
substitutent,
by one to three substitutents per alkyl moiety or by one to three
substitutents per ring,
independently selected from the group consisting of halo, hydroxy, amino, -CN,
(C,-C4)alkyl,
(C,-C4)alkoxy, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]z N-, (C6 C,o)aryl, (C3
Ce)cycloalkyl, (C,-
C,o)heteroaryl and (C,-C,o)heterocyclyl; wherein said (C3-Ce)cycloalkyl and
(C,-
C,o)heterocyclyl may also optionally be substituted by oxo; wherein said (C,-
C,o)heteroaryl
and (C,-C,o)heterocyclyl may optionally be substituted on any ring nitrogen
atom able to
support an additional substitutent by one to two substitutents per ring
independently selected
from the group consisting of (C,-C4)alkyl, (C,-C4)alkyl-(C=O)-, (C6 C,o)aryl,
(C3 CB)cycloalkyl,
(C,-C,o)heteroaryl and (C,-C,o)heterocyclyl;
wherein said R3 group may optionally be taken together with an R4 group to
form a
three to eight membered ring; wherein two of said R4 groups may be taken
together to form a
three to eight membered ring;
R4 wherever it occurs is independently selected from hydrogen and (C,-
C4)alkyl;
G is RS- or Rs-(CHR'3)P ; wherein G is a substituent on any ring carbon atom
of B
capable of forming an additional bond and is oriented at a position other than
alpha to the point
of attachment of the B ring to Y;
p is an integer from one to six;
wherein RS is selected from the group consisting of R'-, R"-O-, R'-(C,-
C4)alkyl-O-,
RB-(C=O)-O-, HaN(C=O)-O-, RB-NH(C=O)-O-, (Re)ZN(C=O)-O-, Rg-S-, R8-(S=O)-, RB-
(SOZ)-,
HZN-(SOZ)-, R8-NH-(SOz)-, (R8)zN-(SOS)-, formyl, R8-(C=O)-, HO-(C=O)-, RB-O-
(C=O)-,
HzN-(C=O)-, RBNH-(C=O)-, (R8)zN-(C=O)-, -NO2, NHz, Re-NH-, (Re)zN-, H(C=O)-
(NR9)-,
RB-(C=O)-(NR9)-, HZN-(C=O)-(NR9)-, ReNH-(C=O)-(NR9)-, (Re)2N-(C=O)-(NR9)-,
R80-(C=O)-(NR9)-, R8-(SOZ)-NH- and R8-(SOz)-(NR9)-;
R6 is selected from the group consisting of perfluoro(C,-C4)alkyl, (C,-
C4)alkenyl, (C,-
C4)alkynyl, R', OH, RB-O-, R8-(C,-C4)alkyl-O-, perfluoro(C,-C4)alkoxy, RB-
(C=O)-O-,
HzN(C=O)-O-, RB-NH(C=O)-O-, (RB)ZN(C=O)-O-, Re-S-, RB-(S=O)-, RB-(SO2)-, HzN-
(SOz)-, Rg-
NH-(SOz)-, (RB)ZN-(SOz)- , formyl, -CN, RB-(C=O)-, HO-(C=O)-, Rg-O-(C=O)-, HZN-
(C=O)-,
RgNH-(C=O)-, (R8)~N-(C=O)-, -NO2, NHz, Rg-NH-, (Re)ZN-, H(C=O)-(NR9)-, R8-
(C=O)-(NR9)-,
SUBSTITUTE SHEET (RULE 26)


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H2N-(C=O)-(NR9)-, ReNH-(C=O)-(NR9)-, (RB)zN-(C=O)-(NR9)-, R80-(C=O)-(NR9)-,
Rg-(SO2)-NH- and RB-(SOz)-(NR9)-;
R' is selected from the group consisting of (C fi C,°)aryl, (C3
CB)cycloalkyl,
(C,-C,°)heteroaryl and (C,-C,°)heterocyclyl; wherein said (C6
C,°)aryl, (C3 Ca)cycloalkyl,
(C,-C,°)heteroaryl and (C,-C,°)heterocyclyl moieties may be
optionally substituted on any of the
ring carbon atoms capable of forming an additional bond by one to three
substituents per ring
independently selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-
C4)perfluoroalkyl, (C,-
C4)pertluoroalkoxy, (C,-C4)alkoxy, amino, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]2 N-
and (C3
CB)cycloalkyloxy; wherein said (C3-Ce)cycloalkyl and (C,-
C,°)heterocyclyl moieties may also
optionally be substituted by oxo; wherein said (C,-C,°)heteroaryl and
(C,-C,°)heterocyclyl
moieties may optionally be substituted on any ring nitrogen atom able to
support an additional
substitutent by one to two substitutents per ring independently selected from
the group
consisting of (C,-C4)alkyl and (C,-C4)alkyl-(C=O)-;
RB is selected from the group consisting of (C,-C4)alkyl, (C6 C,°)aryl,
(C3 C$)cycloalkyl,
(C,-C,°)heteroaryl and (C,-C,°)heterocyclyl; wherein each RB may
be optionally substituted on
any carbon atom able to support an additional substitutent, by one to three
substitutents per
alkyl moiety or by one to three substitutents per ring, independently selected
from the group
consisting of F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-
C4)pertluoroalkoxy,
(C,-C4)alkoxy, and (C3 CB)cycloalkyloxy; wherein said (C3 C$)cycloalkyl and
(C,
C,°)heterocyclyl may also optionally be substituted by oxo; wherein
said (C,-C,°)heteroaryl
and (C,-C,°)heterocyclyl may also optionally be substituted on any ring
nitrogen atom able to
support an additional substitutent by one to two substitutents per ring
independently selected
from the group consisting of (C,-C4)alkyl and (C,-C4)alkyl-(C=O)-; wherein two
of said R8 may
optionally be taken together with the heteroatom to which they are attached to
form a three to
eight membered ring;
R9 wherever it occurs is independently selected from hydrogen and (C,-
C4)alkyl;
wherein said RB and R9 may optionally be taken together with the heteroatoms
to which they are
attached to form a three to eight membered ring;
R'° wherever it occurs is independently selected from hydrogen and (C,-
CQ)alkyl;
R" is selected from the group consisting of (C6 C,°)aryl, (C,-
C,°)heteroaryl and
(C,-C,°)heterocyclyl; wherein said (C6 C,°)aryl, (C,-
C,°)heteroaryl and (C,-C,°)heterocyclyl
moieties may be optionally substituted on any of the ring carbon atoms capable
of forming an
additional bond by one to three substituents per ring independently selected
from F, CI, Br, CN,
OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-CQ)perfluoroalkoxy, (C,-
C4)alkoxy, and (C3
CB)cycloalkyloxy; wherein said (C,-C,°)heterocyclyl may also optionally
be substituted by oxo;
wherein said (C,-C,°)heteroaryl and (C,-C,°)heterocyclyl may
optionally be substituted on any
SUBSTITUTE SHEET (RULE 26)


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-5-
ring nitrogen atom able to support an additional substitutent by one to two
substitutents per
ring independently selected from the group consisting of (C,-Cd)alkyl and (C,-
CQ)alkyl-(C=O)-;
R'~ wherever it occurs is independently selected from hydrogen and (C,-
C4)alkyl;
R'3 is independently selected from hydrogen and (C,-C4)alkyl; wherein R'3 may
optionally be taken together with R6 to form a four to 10 membered ring;
or the pharmaceutically acceptable salts thereof.
The present invention also relates to the pharmaceutically acceptable acid
addition salts
of compounds of the formula I. The acids which are used to prepare the
pharmaceutically
acceptable acid addition salts of the aforementioned base compounds of this
invention are those
which form non-toxic acid addition salts, i.e., salts containing
pharmacologically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,
sulfate, bisulfate,
phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate,
bitartrate, succinate,
maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-
hydroxy-3
naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical
bases that
may be used as reagents to prepare pharmaceutically acceptable base salts of
those
compounds of formula I that are acidic in nature are those that form non-toxic
base salts with
such compounds. Such non-toxic base salts include, but are not limited to
those derived from
such pharmacologically acceptable cations such as alkali metal cations (e-g.,
potassium and
sodium) and alkaline earth metal cations (~, calcium and magnesium), ammonium
or water-
soluble amine addition salts such as N-methylglucamine-(meglumine), and the
lower
alkanolammonium and other base salts of pharmaceutically acceptable organic
amines.
The term "a bond", as used herein in the group Y, means that the groups Ar'
and Z are
directly connected through a carbon-carbon bond so as to form pendent aryl
rings such as
Biphenyl.
The term "alkyl", as used herein, unless otherwise indicated, includes
saturated
monovalent hydrocarbon radicals having straight, branched or cyclic moieties
or combinations
thereof. Alkyl groups, wherever they occur, may be optionally substituted by a
suitable
substituent.
The term "alkenyl", as used herein, unless otherwise indicated, includes
hydrocarbon
radicals containing at least one olefin linkage and having straight, branched
or cyclic moieties or
combinations thereof.
The term "alkynyl", as used herein, unless otherwise indicated, includes
hydrocarbon
radicals containing at least one carbon-carbon triple bond linkage and having
straight, branched
or cyclic moieties or combinations thereof.
SUBSTITUTE SHEET (RULE 26)


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-6-
The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is
as defined
above.
The term "halo", as used herein, unless otherwise indicated, includes
fluorine, chlorine,
bromine or iodine, preferably fluorine or chlorine.
The term "(C=O)" as used herein refers to a carbonyl group. Used in common
with a
nitrogen atom the group refers to amide. Used in common with an oxygen atom,
the group
refers to carboxylic acid derivatives.
The term "aryl", as used herein, unless otherwise indicated, includes an
organic radical
derived from an aromatic hydrocarbon by removal of one or more hydrogens, such
as phenyl,
naphthyl indanyl or tetrahydronaphthyl; optionally substituted by 1 to 3
suitable substituents such
as fluoro, chloro, cyano, nitro, trifluoromethyl, (C,-C6)alkoxy, (C6
C,o)aryloxy, (C3-
Ce)cycloalkyloxy, trifluoromethoxy, difluoromethoxy, or (Ci-C6)alkyl.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes a
mono or
bicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing
1-2 double bonds
and optionally substituted by 1 to 3 suitable substituents as defined below
such as fluoro,
chloro, trifluoromethyl, (C,-C4)alkoxy, (Cs C,o)aryloxy, trifluoromethoxy,
difluoromethoxy or
(C,-C4)alkyl, more preferably fluoro, chloro, methyl, ethyl and methoxy.
The term "heteroaryl", as used herein, unless otherwise indicated, includes an
organic
radical derived from an aromatic heterocyclic compound by removal of one or
more
hydrogens, such as benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-
benzopyranyl,
benzothia,diazine, benzothiazinyl, benzothiazolyl, benzothiophenyl,
benzoxazolyl, chromanyl,
cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl,
indolizinyl, indolyl, 3H-
indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl,
oxadiazolyl, oxazolyl,
phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl,
pyrimidinyl, pyrazolyl, pyrrolyl,
quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl,
thienyl, triazinyl, and
triazolyl, wherein said (C,-C,o)heteroaryl is optionally substituted on any of
the ring carbon
atoms capable of forming an additional bond by one or two suitable
substituents such as F,
CI, Br, CN, OH, (C,-C4)alkyl, (C,-CQ)perfluoroalkyl, (C,-C4)perfluoroalkoxy,
(C,-C4)alkoxy, and
(C3-C8)cycloalkyloxy. The foregoing groups, as derived from the compounds
listed above, can
be C-attached or N-attached where such is possible. For instance, a group
derived from
pyrrole can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
The term "heterocyclyl", as used herein, unless otherwise indicated, includes
an organic
radical derived from a non-aromatic heterocyclic compound by removal of one or
more
hydrogens, such as 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl,
azetidinyl,
SUBSTITUTE SHEET (RULE 26)


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-7-
dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-
dithianyl,
hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl,
isoxazolidinyl,
morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl,
pyrazolidinyl,
pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl,
tetrahydrofuranyl,
tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl,
tetrahydrothiopyranyl,
thiomorpholinyl, thioxanyl, and trithianyl. The foregoing groups, as derived
from the compounds
listed above, can be C-attached or N-attached where such is possible. For
example, a group
derived from piperidine can be piperidin-1-yl (N-attached) or piperidin-4-yl
(C-attached). The
foregoing groups, as derived from the compounds listed above, can be
optionally substituted
where such is possible by a suitable substituent, such as oxo F, CI, Br, CN,
OH, (C,-C4)alkyl,
(C,-C4)perfluoroalkyl, (C,-CQ)perfluoroalkoxy, (C,-Cd)alkoxy, and (C3
CB)cycloalkyloxy.
"A suitable substituent" is intended to mean a chemically and pharmaceutically
acceptable functional group i.e., a moiety that does not negate the inhibitory
activity of the
inventive compounds. Such suitable substituents may be routinely selected by
those skilled in
the art. Illustrative examples of suitable substituents include, but are not
limited to halo groups,
perfluoroalkyl groups, perfluoroalkoxy groups, alkyl groups, hydroxy groups,
oxo groups,
mercapto groups, alkylthio groups, alkoxy groups, aryl or heteroaryl groups,
aryloxy or
heteroaryloxy groups, aralkyl or heteroaralkyl groups, aralkoxy or
heteroaralkoxy groups,
carboxy groups, amino groups, alkyl- and dialkylamino groups, carbamoyl
groups, alkylcarbonyl
groups, alkoxycarbonyl groups, alkylaminocarbonyl groups dialkylamino carbonyl
groups,
arylcarbonyl groups, aryloxycarbonyl groups, alkylsulfonyl groups, an
arylsulfonyl groups and the
like.
The phrase "capable of forming an additional bond" refers to the replacement
of a
hydrogen radical with another higher radical.
The phrase "oriented at a position other than alpha to the point of attachment
of the B
ring to Y" refers to substitution at the position adjacent to the bridgehead
atom connecting to the
Y group. If B is phenyl then substitution of the identified group can not be
in the ortho position
(i.e. relative to the connection of phenyl to Y).
Some compounds of formula I contain chiral centers and therefore exist in
different
enantiomeric forms. This invention relates to all optical isomers,
enantiomers, diasteriomers and
stereoisomers of the compounds of formula I and mixtures thereof. The
compounds of the
invention also exist in different tautomeric forms. This invention relates to
all tautomers of
formula I. Those skilled in the art are well aware that the pyrimidine-2,4,6-
trione nucleus exists
as a mixture of tautomers in solution. The various ratios of the tautomers in
solid and liquid form
is dependent on the various substituents on the molecule as well as the
particular crystalization
technique used to isolate a compound.
SUBSTITUTE SHEET (RULE 26)


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-g_
An embodiment of the invention includes those compounds of formula I wherein X
is
>C=0 more preferably wherein Y is a bond, oxygen, sulfur, -CHz , >S02, -OCHZ
or -CHzO-,
more preferably wherein Y is oxygen, -OCH2 or -CHzO-, most preferably wherein
Y is oxygen.
Preferred compounds of the invention include those wherein X is oxygen, -OCHZ
,
-CHzO-, more preferably wherein X is oxygen; more preferably wherein Y is a
bond, oxygen,
sulfur, -CHZ , >S02, -OCHz or -CHZO-, more preferably wherein Y is oxygen, -
OCHz or -CHzO-,
most preferably wherein Y is oxygen.
Other embodiments of the invention include those compounds of formula I
wherein X is
sulfur, >S02, >S=0, -SCHZ , -CHzS-, -(O=S)CHZ , -CH2(S=O)-,-CHZSOz or -S02CHz
, more
preferably wherein Y is a bond, oxygen, sulfur, -CH2 , >SOZ, -OCHZ or -CH20-,
more preferably
wherein Y is oxygen, -OCHZ or -CHzO-, most preferably wherein Y is oxygen.
Other embodiments of the invention include those compounds of formula I
wherein X is
>NR'°, -CHzN(R'°)- or -N(R'°)CHz , more preferably
wherein Y is a bond, oxygen, sulfur, -CH2 ,
>S02, -OCHz or -CHzO-, more preferably wherein Y is oxygen, -OCHZ or -CHzO-,
most
preferably wherein Y is oxygen.
Other embodiments of the invention include those compounds of formula I
wherein X is
-N(R'°)SOz or -SOzN(R'°)-, more preferably wherein Y is a bond,
oxygen, sulfur, -CHZ , >SOz,
-OCHZ or -CHzO-, more preferably wherein Y is oxygen, -OCHZ , most preferably
wherein Y is
oxygen.
Other preferred compounds are those wherein A is optionally substituted
phenyl.
Other embodiments of the present invention include those compounds wherein A
is (C,-
C,°)heteroaryl; preferably pyridyl, furyl, pyrroyl, thienyl,
isothiazolyl, imidazolyl, benzimidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl,
isobenzofuryl, benzothienyl,
pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl,
oxazolyl, benzthiazolyl or
benzoxazolyl, more preferably pyridinyl, pyridazinyl, pyrazinyl, pyrimidyl,
most preferably pyridyl
optionally substituted by 1 to 3 suitable substituents, such as tluoro,
chloro, trifluoromethyl, (C,-
C6)alkoxy, (C6 C,°)aryloxy, trifluoromethoxy, difluoromethoxy or (C,-
C6)alkyl.
Other preferred compounds are those wherein B is optionally substituted
phenyl.
Other embodiments of the invention include those compounds of formula I
wherein B is
(C,-C,°)heteroaryl(C,-C4)alkyl or (C,-C,°)heteroaryl, preferably
(C,-C,°)heteroaryl; wherein said
(C,-C,°)heteroaryl is optionally substituted with one or more
substituents, preferably zero, one or
two substituents, independently selected from F, CI, Br, -CN, OH, (C,-
C4)alkyl, (C,-
CQ)perfluoroalkyl, (C,-C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3
CB)cycloalkyloxy.
Other embodiments of the invention include those compounds of formula I
wherein B is
a (C,-C,°)heterocyclyl group such as tetrahydrofuranyl,
tetrahydropyranyl, N-methyl-3-
azetidinyl, piperazinyl, piperidinyl, 1,3-oxazolidin-4-on-5-yl, 1,3-oxazolidin-
2,4-dion-5-yl, 4,5-
SUBSTITUTE SHEET (RULE 26)


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_g_
dihydro-1,2-oxazolidin-3-on-4-yl, 1,3-thiazolidin-4-on-5-yl, 1,3-thiazolidin-
2,4-dion-5-yl,
1,3-imidazolidin-4-on-5-yl, 1,3-imidazolidin-2,4-dion-5-yl, 1,2-pyrazolidin-3-
on-4-yl,
tetrahydro-1,3-oxazin-4-on-5-yl, tetrahydro-1,3-oxazin-2,4-dion-5-yl,
morpholinyl,
morpholin-3-on-2-yl, morpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-oxazin-3-on-2-
yl,
tetrahydro-1,3-thiazin-4-on-5-yl, tetrahydro-1,3-thiazin-2,4-dion-5-yl,
thiomorpholinyl,
thiomorpholin-3-on-2-yl, thiomorpholin-3,5-dion-2-yl, 2,3-dihydro-1,4-thiazin-
3-on-2-yl,
hexahydro-1,2-diazin-3-on-4-yl, 4,5-dihydro-2H-pyridazin-3-on-4-yl,
hexahydro-1,3-diazin-2,4-dion-5-yl, piperazin-2-on-3-yl, piperazin-2,6-dion-3-
yl,
tetrahydro-1,3,4-thiadiazin-5-on-6-yl, 5,6-dihydro-1,3,4-thiadiazin-5-on-6-yl,
1,3,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1,2,4-oxadiazin-5-on-6-yl,
tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 1,2,4-triazin-5-on-6-yl,
tetrahydro-1,2,4-oxadiazin-5-on-6-yl, 5,6-dihydro-1-2,4-oxadiazin-5-on-6-yl,
1,2,4-oxadiazin-3,5-dion-6-yl, and 1,2,4-triazin-6-on-5-yl; preferably
tetrahydrofuranyl,
tetrahydropyranyl, N-methyl-3-azetidinyl, piperazinyl, piperidinyl, N-
methylpiperidinyl and
morpholinyl; more preferably tetrahydrofuranyl and tetrahydropyranyl; most
preferably
tetrahydrofuran-2-yl and tetrahydropyran-2-yl. One skilled in the art will
appreciate that the
numbering scheme used throughout this specification is in accordance with
standard
nomenclature practice beginning numbering at the heaviest atom.
Other embodiments of the invention include those compounds of formula I
wherein B is
(C3 C,o)cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexy or cycloheptyll;
preferably cyclohexyl or cycloheptyl.
Other embodiments of the invention include those compounds of formula I
wherein G is
RS- wherein R5 is HZN-(C=O)-, RBNH-(C=O)-, (Re)zN-(C=O)-, NHz, RB-NH-, (Re)zN-
,
R8-(C=O)-(NR9)-, H2N-(C=O)-(NR9)-, ReNH-(C=O)-(NR9)-, (RB)zN-(C=O)-(NR9)-,
R80-(C=O)-(NR9)-, R8-(SOz)-NH-, R8-(SOZ)-(NR9)- RB-(SOZ)-, and H2N-(SOz)-;
preferably
HZN-(C=O)-, ReNH-(C=O)-, (R8)zN-(C=O)-, NH2, RB-NH-, (R8)zN-, and RB-(C=O)-
(NR9)-, more
preferably wherein Re is (C,-C4)alkyl (preferably methyl).
Other preferred compounds of the invention wherein G is RS-, wherein RS
contains an Re
group, are those wherein RB is (C,-C4)alkyl or (C3 CB)cycloalkyl optionally
substituted on any of
the ring carbon atoms capable of forming an additional bond by one to three
substituents per ring
independently selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-
C4)perfluoroalkyl, (C,-
C4)perfluoroalkoxy, (C,-C4)alkoxy, and (C3-CB)cycloalkyloxy; preferably (C,-
CQ)alkyl and (C,-
C4)alkoxy.
Preferred compounds of the invention include those compounds wherein G is RS-,
wherein RS- is HzN-(C=O)-, ReNH-(C=O)-, (Re)zN-(C=O)- or R8-(C=O)-(NR9)-. More
preferred
compounds of the invention include those compounds of the invention wherein G
is RS-, wherein
SUBSTITUTE SHEET (RULE 26)


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-10-
RS- is RBNH-(C=O)- or (R8)2N-(C=O)-. Most preferred compounds wherein G is RS-
, wherein RS-
contains R8, are those compounds wherein Re is methyl.
Most preferred embodiments of the invention include those compounds of formula
I
wherein G is RS- wherein R5 is R'- or R'-(C,-C4)alkyl-O-; wherein R' is
preferably (Cs C,o)aryl,
(C3 C,o)cycloalkyl or (C,-C,o)heteroaryl; optionally substituted on any of the
ring carbon atoms
capable of forming an additional bond by one to three substituents per ring
independently
selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-
C4)perfluoroalkoxy, (C,
C4)alkoxy, amino, (C,-C4)alkyl-NH-, [(C,-CQ)alkyl]2-N- and (C3
CB)cycloalkyloxy. More
preferred embodiments of the invention include those compounds of formula I
wherein G is RS-,
wherein RS is R'-, wherein R' is (C,-C,o)heteroaryl.
Another embodiment of the invention of interest to the inventors are those
compounds
wherein G is RS-, wherein R5 is R'-, wherein R' is (C6 C,o)aryl, more
preferably phenyl.
Embodiments of the invention wherein G is -R5, wherein RS is R'- or R'-(C,-
C4)alkyl-O-;
include those compounds wherein R' is (C,-C,o)heteroaryl selected from
thegroup consisting of
pyridyl, furyl, pyrroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl,
tetrazolyl, pyrazinyl,
pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl,
pyrazolyl, indolyl,
isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl,
benzthiazolyl or benzoxazolyl, more
preferably pyridyl, pyrimidyl, triazole, diazole, oxazole, oxadiazole, pyrrole
or thiazole; wherein
each of said (C,-C,o)heteroaryl may optionally be substituted by 1 to 3
suitable substituents,
such as tluoro, chloro, tritluoromethyl, (C,-C6)alkoxy, (C6 C,o)aryloxy,
trifluoromethoxy,
difluoromethoxy and (C,-C6)alkyl.
Preferred (C,-C,o)heteroaryl includes five membered heteroaryls such as
triazoles,
diazoles, oxazoles, oxadiazoles, pyrroles and thiazoles; preferably 1,2,4-
triazol-1-yl,
1,2,4-triazol-3-yl, 1,3,4-triazol-1-yl, 1,3-diazol-1-yl, 1,2-diazol-3-yl, 1,2-
diazol-1-yl,
1,2-diazol-4-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-oxazol-5-yl, 1,2,4-
oxadiazol-3-yl, 1,3,4-
oxadiazol-2-yl, pyrrol-1-yl, 1,3-thiazol-4-yl and 1,3-thiazol-2-yl; optionally
substituted with (C ,-
C4)alkyl, amino, (C,-C4)alkyl-NH-, [(C,-CQ)alkyl]z-N-, halo or hydroxy,
preferably with (C,-
C4)alkyl, more preferably methyl. Most preferred (C,-C,o)heteroaryl includes
1,3,4-oxadiazolyl
optionally substituted with (C,-C~)alkyl.
Other embodiments of the invention include those compounds of formula I
wherein G is
-R5, wherein RS is R"-O- or Re-(C=O)-O-. Other compounds of interest to the
present inventors
include those compounds wherein RS contains R", wherein R" is (Cs C,o)aryl or
(C,-
C,o)heteroaryl optionally substituted on any of the ring carbon atoms capable
of forming an
additional bond by one to three substituents independently selected from F,
CI, Br, CN, OH, (C,-
C4)alkyl, (C,-C4)perfluoroalkyl, (C,-C4)perfluoroalkoxy, (C,-CQ)alkoxy and (C3
CB)cycloalkyloxy;
preferably CN, (C,-C4)alkyl, amino, (C,-C4)alkyl-NH- and [(C,-C4)alkyl]2-N-.
SUBSTITUTE SHEET (RULE 26)


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Other embodiments of the invention include those compounds of formula I
wherein G is
-RS wherein RS is Re-O-(C=O)- or RB-(C=O)-.
Other embodiments of the invention include those compounds of formula I
wherein G is
-RS wherein RS is RB-S-, Rg-(S=O)-, R8-(SOZ)-, RB-NH-(SOz)- or (Rg)zN-(SOz)-.
Other preferred embodiments of the invention include those compounds of
formula I
wherein G is R6-(CHR'3)P , preferably wherein p is an integer from one to six;
are those wherein
R6 is selected from the group consisting of (C,-C4)alkenyl, (C,-C4)alkynyl, -
CN, -NO2, OH, NH2,
perfluoro(C,-C4)alkoxy, HEN-(SOz)-, HzN-(C=O)-, Rg-NH-(C=O)-, (R8)Z (C=O)- and
NHZ (C=O)-(NR9)-; preferably wherein R6 is -CN, OH, NH2, HzN-(C=O)- or NHz
(C=O)-(NR9)-;
most preferably wherein R6 is HzN-(C=O)- or -CN.
Other preferred embodiments of the invention include those compounds of
formula I
wherein G is R6-(CHR'3)P , preferably wherein p is an integer from one to six;
are those wherein
R6 is selected from the group consisting of (Cs C,o)aryl, (C3 Ca)cycloalkyl,
(C,-C,o)heteroaryl and
(C,-C,o)heterocyclyl. More preferred compounds of the invention are those
wherein R6 is (C,-
C,o)heteroaryl optionally substituted with zero to three substitutents
independently selected from
halo or (C,-C4)alkyl.
Other preferred embodiments of the invention include those compounds of
formula I
wherein G is R6-(CHR'3)P , preferably wherein p is an integer from one to six;
are those wherein
R6 contains an R8 group such as Re-O-, Re-(C,-Cd)alkyl-O-, RB-NH-, (RB)2N- R8-
S-, Re-(S=O)-, RB-
(SOz)-, Re-(SOz)-NH-, R8-(SO2)-(NR9)-, Rg-NH-(SOZ)-, (RB)zN-(SOZ)-, HEN-(C=O)-
(NR9)-,
RBNH-(C=O)-(NR9)-, (Rg)zN-(C=O)-(NR9)-, R80-(C=O)-(NR9)-, RB-(C=O)-(NR9)-, Re-
(C=O)-O-,
R~-O-(C=O)- and R8-(C=O)-. More preferred compounds of the invention are those
wherein RB is
-(C,-C4)alkyl or (C3 C6)cycloalkyl optionally substituted with one to three
substitutents
independently selected from halo or (C,-C4)alkoxy.
Other compounds of interest within the scope of the invention include those
compounds
wherein G is R6-(CHR'3)P , and R6 contains an R8 group are those wherein R8 is
(C,-C,o)heteroaryl, (C fi C,o)aryl or (C,-C,o)heterocyclyl,optionally
substituted on any of the ring
carbon atoms capable of forming an additional bond by one to three
substituents independently
selected from F, CI, Br, CN, OH, (C,-C4)alkyl, (C,-C4)perfluoroalkyl, (C,-
C4)perfluoroalkoxy, (C,
C4)alkoxy, and (C3 Cg)cycloalkyloxy; preferably (C,-C4)alkyl and (C,-
C4)alkoxy.
Most preferred -R6 substituents containing an Rg group are RBNH-(C=O)-(NR9)-,
(RB)zNH-(C=O)-(NR9)-, R80-(C=O)-(NR9)- and RB-(C=O)-(NR9)-, more preferably
wherein R8 is
(C,-C4)alkyl, more preferably methyl.
Other embodiments of the present invention include those wherein A and B are
substituted on any of the ring carbon atoms capable of forming an additional
bond by one or
SUBSTITUTE SHEET (RULE 26)


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more substituents independently selected from F, CI, Br, -CN, OH, (C,-
C4)alkyl, (C,-
C4)pertluoroalkyl, (C,-C4)perfluoroalkoxy, (C,-C4)alkoxy and (C3
C8)cycloalkyloxy.
Other embodiments of the invention include those compounds of formula I
wherein R' is
(C3 Ce)cycloalkyl wherein said (C3 CB)cycloalkyl may also optionally be
substituted by one to two
substituents independently selected from halo, (C,-C4)alkyl, (C,-C4)alkenyl,
(C,-C4)alkynyl, R3-,
R3-O-, perfluoro(C,-C4)alkoxy, R3-(C,-C4)alkyl-O-, R3-(C=O)-O-, -NOZ, (R3)2N-,
R3-(C=O)-(NR°)-,
R3-S-, R3-(S=O)-, R3-(SOz)-, R3-(SOZ)-(NR4)-, R3-NH-(SOZ)-, (R3)2N-(SOZ)-, -
CN, R3-(C=O)-,
R3-O-(C=O)- and (R3)ZN-(C=O)-.
Other embodiments of the invention include those compounds of formula I
wherein R'
is (RZ)a"+,-(C)~- and n is an integer from one to ten; each R2 is
independently selected from the
group consisting of halo, R3-, (C,-C4)alkenyl, (C,-CQ)alkynyl, R3-O-,
pertluoro(C,-C4)alkoxy,
R3-(C=O)-O-, (R3)2N-(C=O)-O-, -NOZ, (R3)zN-, R3-(SO2)-(NR4)-, R3-(C=O)-(NR4)-,
R30-(C=O)_
(NR4)-, (R3)2-N-(C=O)-(NR4)-, R3-S-, R3-(S=O)-, R3-(SOz)-~ (R3)ZN-(SOZ)-, -CN,
R3-(C=O)-, R3-O_
(C=O)- and (R3)zN-(C=O)-; wherein not more than three of said Rz substituents
may be other
than hydrogen and any one carbon atom of said -(C)~ group can contain only one
bond to a
heteroatom; and each R3 is independently selected from the group consisting of
hydrogen,
(C,-Ca)alkyl, (C6 C,o)aryl, (C3-Ce)cycloalkyl, (C,-C,o)heteroaryl and (C,-
C,o)heterocyclyl;
wherein each R3 may be optionally substituted by one to three substitutents
independently
selected from the group consisting of halo, hydroxy, amino, -CN, (C,-C4)alkyl,
(C,-C4)alkoxy,
(C,-C4)alkyl-NH-, [(C,-C4)alkyl]z N- (C6-C,o)aryl, (C3-C8)cycloalkyl, (C,-
C,o)heteroaryl and (C,-
C,o)heterocyclyl; wherein said R3 group may optionally be taken together with
R4 to form a
three to eight membered ring.
Other embodiments of the invention include those compounds of formula I
wherein R' is
(Rz)z~+,-(C)~ , n is an integer from one to ten; at least one RZ is
independently selected from the
group consisting of R3-, R3-O-, R3-(C=O)-O-, R3-S-, R3-(S=O)-, R3-(SOZ)-,
(R3)ZN-,
R3-(SO2)-(NR4)-, R3-NH-(SOZ)-, (R3)zN-(SOZ)-, R3-(C=O)-(NR4)-, R3-O-(C=O)- and
R3-(C=O)-;
and each R3 is independently selected from the group consisting of hydrogen
and (C,-C4)alkyl;
wherein each R3 (C,-CQ)alkyl moiety may be optionally substituted by one to
three
substitutents independently selected from the group consisting of halo,
hydroxy, amino, -CN,
(C,-C4)alkyl, (C,-C4)alkoxy, (C,-C4)alkyl-NH-, [(C,-CQ)alkyl]2 N- (C6
C,o)aryl, (C3 Ce)cycloalkyl,
(C,-C,o)heteroaryl and (C,-C,o)heterocyclyl; wherein said R3 group may
optionally be taken
together with Rø to form a three to eight membered ring.
Other embodiments of the invention include those compounds of formula I
wherein R' is
(RZ)2~+,-(C)~ , n is an integer from one to ten; and each Rz is independently
selected from the
group consisting of hydrogen, halo, (C,-CQ)alkyl, R3- and R3-O-.
SUBSTITUTE SHEET (RULE 26)


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Other embodiments of the invention include those compounds of formula 1
wherein n is
one to three; and each R3 is independently selected from the group consisting
of hydrogen
and (C,-C4)alkyl; wherein each R3 (C,-C4)alkyl moiety may be optionally
substituted by one to
three substitutents independently selected from the group consisting of halo,
hydroxy, amino,
-CN, (C,-CQ)alkyl, (C,-CQ)alkoxy, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]2 N- (C6
C,p)aryl, (C3-
CB)cycloalkyl, (C,-C,o)heteroaryl and (C,-C,o)heterocyclyl.
Other embodiments of the invention include those compounds of formula I
wherein n is
one to three; and each R3 is independently selected from the group consisting
of hydrogen
and (C,-C4)alkyl; wherein at least one R3 (C,-C4)alkyl group is substituted by
halo, hydroxy,
amino, -CN, (C,-C4)alkyl, (C,-C4)alkoxy, (C,-C4)alkyl-NH-, [(C,-C4)alkyl]2-N-
(C6 C,o)aryl, (C3
CB)cycloalkyl, (C,-C,o)heteroaryl and (C,-C,o)heterocyclyl.
Other embodiments of the invention include those compounds of formula I
wherein n is
one; and each R3 is independently selected from the group consisting of
hydrogen and (C,
C4)alkyl; wherein at least one R3 (C,-C4)alkyl group is substituted by (C,-
C4)alkoxy, (C,
C4)alkyl-NH-, or [(C,-C4)alkyl]z N-.
Other embodiments of the invention include those compounds of formula I
wherein at
least one of said R3 groups is (Cs C,o)aryl, (C3-CB)cycloalkyl, (C,-
C,o)heteroaryl or (C,-
C,o)heterocyclyl; wherein each of said R3 groups may be optionally substituted
by one to three
substitutents independently selected from the group consisting of halo,
hydroxy, amino, -CN,
(C,-C4)alkyl, (C,-C4)alkoxy, (C,-C4)alkyl-NH-, [(C,-CQ)alkyl]z N- (C6
C,o)aryl, (C3 Ce)cycloalkyl,
(C,-C,o)heteroaryl and (C,-C,o)heterocyclyl.
More preferred R' is (C,-C4)alkoxy(C,-CQ)alkyl, most preferably ethoxyethyl.
More preferred compounds of the invention include compounds of formula I,
wherein X
is oxygen, Y is a bond, oxygen, sulfur, -CHz , >S02, -OCHZ or -CHZO-; R' is
(Rz)z~+,-(C)~ , n is
one; and each R2 is independently selected from the group consisting of
hydrogen and
(C,-CQ)alkyl; wherein at least one R3 (C,-C4)alkyl group is substituted by (C,-
CQ)alkoxy,
(C,-C4)alkyl-NH- or [(C,-C4)alkyl]2 N-.
Most preferred compounds of the invention include those wherein X is oxygen; Y
is
oxygen; A and B are each independently optionally substituted phenyl; G is
optionally substituted
phenyl and R' is (RZ)z~+,-(C)~ , n is one; each RZ is independently selected
from the group
consisting of hydrogen, (C,-C4)alkyl, R3- and R3-O- and each R3 is
independently selected from
the group consisting of hydrogen and (C,-C4)alkyl; wherein one R3 (C,-CQ)alkyl
group is
substituted by (C,-C4)alkoxy.
Other most preferred compounds of the invention include those wherein X is
oxygen; Y
is oxygen; and A and B are each optionally substituted phenyl; G is optionally
substituted (C,-
C,o)heteroaryl and R' is (RZ)2""-(C)~-, n is one; each Rz is independently
selected from the
SUBSTITUTE SHEET (RULE 26)


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group consisting of hydrogen, (C,-C4)alkyl, R3- and R3-O- and each R3 is
independently
selected from the group consisting of hydrogen and (C~-CQ)alkyl; wherein one
R3 (C,-C4)alkyl
group is substituted by (C~-C4)alkoxy.
Other more preferred compounds of the invention include those wherein X is
oxygen; Y
is oxygen; and A and B are each optionally substituted phenyl; G is optionally
substituted (C3
CB)cycloalkyl and R' is (RZ)2~+,-(C)~-, n is one; each R2 is independently
selected from the group
consisting of hydrogen, (C,-C4)alkyl, R3- and R3-O- and each R3 is
independently selected from
the group consisting of hydrogen and (C,-C4)alkyl; wherein one R3 (C,-CQ)alkyl
group is
substituted by (C,-CQ)alkoxy.
Most preferred compounds of the invention include those wherein X is oxygen; Y
is
oxygen; and A and B are each optionally substituted phenyl; G is R6-(CHR9)P
and R' is
(RZ)2~+,-(C)~ , n is one; each RZ is independently selected from the group
consisting of hydrogen,
(C,-C4)alkyl, R3- and R3-O- and each R3 is independently selected from the
group consisting of
hydrogen and (C,-C4)alkyl; wherein one R3 (C,-C4)alkyl group is substituted by
(C,-C4)alkoxy.
Specific preferred compounds of formula I are selected from the group
consisting of:
5-(2-Ethoxy-ethyl)-5-[4-(4-thiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(1-methyl-1 H-pyrazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(4-{4-(5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

phenyl)-pentanenitrile;
5-(2-Ethoxy-ethyl)-5-{4-[4-(2-methyl-thiazol-4-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(1 H-pyrazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-[4-(4-oxazol-5-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione; and
5-(2-Ethoxy-ethyl)-5-[4-(4-pyrimidin-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione
or pharmaceutically acceptable salts thereof.
Other compounds of the invention include:
5-[4-(Biphenyl-4-yloxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione;
5-[4-(Biphenyl-3-yloxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione;
N-(3-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

phenyl)-acetamide;
5-(2-Ethoxy-ethyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-
2,4,6-
trione;
SUBSTITUTE SHEET (RULE 26)


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5-(2-Ethoxy-ethyl)-5-[4-(4-[1,2,4]triazol-1-yl-phenoxy)-phenoxy]-pyrimidine-
2,4,6-
triune;
5-[4-(4-Aminomethyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-
triune;
5-(2-Ethoxy-ethyl)-5-[4-(4-imidazol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
triune;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-acetamide;
4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzamide;
4'-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
biphenyl-
4-carbonitrile;
5-(2-Ethoxy-ethyl)-5-[4-(4-methanesulfonyl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
triune;
4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N-
methyl-
benzamide;
4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
N,N-
dimethyl-benzamide;
5-(2-Ethoxy-ethyl)-5-[4-(4-oxazol-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
triune;
5-{4-[4-(5-Dimethylamino-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-(2-ethoxy-
ethyl)-pyrimidine-2,4,6-triune;
5-(2-Ethoxy-ethyl)-5-[4-(4-pyrrol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
triune;
5-(2-Ethoxy-ethyl)-5-{4-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-triune;
5-(2-Ethoxy-ethyl)-5-{4-[4-(5-methyl-isoxazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-triune;
5-(2-Ethoxy-ethyl)-5-[4-(6-tluoro-biphenyl-3-yloxy)-phenoxy]-pyrimidine-2,4,6-
triune;
2-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

phenyl)-acetamide;
5-(2-Ethoxy-ethyl)-5-[4-(4-[1,2,4]triazol-4-yl-phenoxy)-phenoxy]-pyrimidine-
2,4,6-
triune
5-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-
triune;
5-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-
triune;
N-[2-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-
phenoxy}-
phenyl)-ethyl]-acetamide;
5-(2-Ethoxy-ethyl)-5-{4-[4-(4H-[1,2,4]triazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-
triune;
5-(2-Ethoxy-ethyl)-5-[4-(4-hydroxymethyl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
triune;
SUBSTITUTE SHEET (RULE 26)


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-16-
5-(2-Ethoxy-ethyl)-5-{4-[4-(5-ethyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-trione;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-3-methyl-butyramide;
Pentanoic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-
yloxy]-
phenoxy}-benzylamide;
5-(2-Ethoxy-ethyl)-5-[4-(4-thiazol-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-isobutyramide;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-2-methoxy-acetamide;
Cyclobutanecarboxylic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-
pyrimidin-
5-yloxy]-phenoxy}-benzylamide;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-2-methyl-butyramide;
N-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-propionamide;
5-(2-Ethoxy-ethyl)-5-[4-(3-methyl-4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-
pyrimidine-2,4,6-trione
5-(2-Ethoxy-ethyl)-5-{4-[3-methyl-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-
phenoxy}-pyrimidine-2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-[4-(4-pyrazol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-(2-Ethoxy-ethyl)-5-{4-[3-methyl-4-(1 H-pyrazol-4-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-{4-[3-methyl-4-(1-methyl-1 H-pyrazol-4-yl)-phenoxy]-
phenoxy}-
pyrimidine-2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-{4-[4-(1 H-pyrazol-4-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
1-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-3-methyl-urea;
5-(2-Ethoxy-ethyl)-5-[4-(3-fluoro-4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-
pyrimidine-2,4,6-trione;
5-(2-Ethoxy-ethyl)-5-{4-[3-fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-
phenoxy}-pyrimidine-2,4,6-trione;
5-{4-[3-Fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-
(tetrahydro-
furan-3-yl)-pyrimidine-2,4,6-trione;
SUBSTITUTE SHEET (RULE 26)


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5-{4-[3-Fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-
(tetrahydro-
pyran-3-yl)-pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-(tetrahydro-furan-
3-yl)-
pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-(tetrahydro-pyran-
3-yl)-
pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-(tetrahydro-pyran-
2-
ylmethyl)-pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-(tetrahydro-furan-
2-
ylmethyl)-pyrimidine-2,4,6-trione;
5-{4-[3-Fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-
(tetrahydro-
furan-2-ylmethyl)-pyrimidine-2,4,6-trione;
5-{4-[3-Methyl-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-
(tetrahydro-
furan-2-ylmethyl)-pyrimidine-2,4,6-trione;
5-(4-Methyl-5-oxo-morpholin-2-ylmethyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-

phenoxy]-pyrimidine-2,4,6-trione;
5-(4-Methyl-3-oxo-morpholin-2-ylmethyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-

phenoxy]-pyrimidine-2,4,6-trione;
N-Isopropyl-2-{5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-2,4,6-trioxo-
hexahydro-pyrimidin-5-yl}-acetamide;
N-(2-{5-[4-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-phenoxy]-2,4,6-trioxo-hexahydro-
pyrimidin-5-yl}-ethyl)-isobutyramide;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-pyridin-2-
ylmethyl-
pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-pyridin-3-
ylmethyl-
pyrimidine-2,4,6-trione;
5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-pyridin-4-
ylmethyl-
pyrimidine-2,4,6-trione;
5-{4-[6-(5-Methyl-[1,3,4]oxadiazol-2-yl)-pyridin-3-yloxy]-phenoxy}-5-
(tetrahydro-furan-
2-ylmethyl)-pyrimidine-2,4,6-trione;
5-[4-(4-Oxazol-2-yl-phenoxy)-phenoxy]-5-(tetrahydro-furan-2-ylmethyl)-
pyrimidine-
2,4,6-trione;
5-{4-[4-(2-Oxo-pyrrolidin-1-ylmethyl)-phenoxy]-phenoxy}-5-(tetrahydro-furan-2-
ylmethyl)-pyrimidine-2,4,6-trione;
Cyclobutanecarboxylic acid 4-{4-[2,4,6-trioxo-5-(tetrahydro-furan-2-ylmethyl)-
hexahydro-pyrimidin-5-yloxy]-phenoxy}-benzylamide;
SUBSTITUTE SHEET (RULE 26)


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5-[4-(4-Pyrazol-1-ylmethyl-phenoxy)-phenoxy]-5-(tetrahydro-furan-2-ylmethyl)-
pyrimidine-2,4,6-trione;
(5-{4-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-2,4,6-trioxo-
hexahydro-
pyrimidin-5-yl)-acetic acid;
(5-{4-[3-Methyl-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-2,4,6-
trioxo-
hexahydro-pyrimidin-5-yl)-acetic acid;
(5-{4-[3-Fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-2,4,6-
trioxo-
hexahydro-pyrimidin-5-yl)-acetic acid;
3-{5-[4-(4-([1,3,4]-Oxadiazol-2-yl)-phenoxy)-phenoxy]-2,4,6-trioxo-hexahydro-
pyrimidin-5-yl}-N,N-dimethyl-propionamide;
5-[4-(Biphenyl-4-yloxy)-phenoxy]-5-(cyclohexyl)-pyrimidine-2,4,6-trione;
5-[4-(Biphenyl-3-yloxy)-phenoxy]-5-(cyclohexyl)-pyrimidine-2,4,6-trione;
N-(3-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
phenyl)-
acetamide;
5-(cyclohexyl)-5-[4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-
2,4,6-
trione;
5-(cyclohexyl)-5-[4-(4-[1,2,4]triazol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-[4-(4-Aminomethyl-phenoxy)-phenoxy]-5-(cyclohexyl)-pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-imidazol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-
acetamide;
4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzamide;
4'-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
biphenyl-4-
carbonitrile;
5-(cyclohexyl)-5-[4-(4-methanesulfonyl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N-
methyl-
benzamide;
4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N,N-
dimethyl-
benzamide;
5-(cyclohexyl)-5-[4-(4-oxazol-5-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-oxazol-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
5-{4-[4-(5-Dimethylamino-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-5-
(cyclohexyl)-
pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-pyrrol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-{4-[4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
SUBSTITUTE SHEET (RULE 26)


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5-(cyclohexyl)-5-{4-[4-(5-methyl-isoxazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
5-(cyclohexyl)-5-[4-(6-fluoro-biphenyl-3-yloxy)-phenoxy]-pyrimidine-2,4,6-
trione;
2-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
phenyl)-
acetamide;
5-(cyclohexyl)-5-[4-(4-[1,2,4]triazol-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione
5-(cyclohexyl)-5-{4-[4-(1 H-pyrazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-
trione;
5-(cyclohexyl)-5-{4-[4-(2-methyl-thiazol-4-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
5-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
phenyl)-
pentanenitrile;
5-[4-(4-Cyclopentyl-phenoxy)-phenoxy]-5-(cyclohexyl)-pyrimidine-2,4,6-trione;
5-[4-(4-Cyclohexyl-phenoxy)-phenoxy]-5-(cyclohexyl)-pyrimidine-2,4,6-trione;
N-[2-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
phenyl)-ethyl]-acetamide;
5-(cyclohexyl)-5-{4-[4-(4H-[1,2,4]triazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-
2,4,6-
trione;
5-(cyclohexyl)-5-{4-[4-(1-methyl-1 H-pyrazol-3-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(cyclohexyl)-5-{4-[4-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-phenoxy}-pyrimidine-

2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-hydroxymethyl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-(cyclohexyl)-5-{4-[4-(5-ethyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-3-
methyl-butyramide;
Pentanoic acid 4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-
phenoxy}-benzylamide;
5-(cyclohexyl)-5-[4-(4-thiazol-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-
isobutyramide;
N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-2-
methoxy-acetamide;
Cyclobutanecarboxylic acid 4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-
pyrimidin-5-
yloxy]-phenoxy}-benzylamide;
SUBSTITUTE SHEET (RULE 26)


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N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-2-
methyl-butyramide;
N-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-
propionamide;
5-(cyclohexyl)-5-[4-(4-thiazol-2-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-pyrimidin-4-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-
trione;
5-(cyclohexyl)-5-[4-(3-methyl-4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-
pyrimidine-
2,4,6-trione;
5-(cyclohexyl)-5-{4-[3-methyl-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-
phenoxy}-
pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-[4-(4-pyrazol-1-yl-phenoxy)-phenoxy]-pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-{4-[3-methyl-4-(1 H-pyrazol-4-yl)-phenoxy]-phenoxy}-
pyrimidine-
2,4,6-trione;
5-(cyclohexyl)-5-{4-[3-methyl-4-(1-methyl-1 H-pyrazol-4-yl)-phenoxy]-phenoxy}-
pyrimidine-2,4,6-trione;
5-(cyclohexyl)-5-{4-[4-(1 H-pyrazol-4-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-
trione;
1-(4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-3
methyl-urea;
1-(4-{4-[5-(cyclohexyl )-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-
benzyl)-3-
propyl-urea; and
Azetidine-1-carboxylic acid 4-{4-[5-(cyclohexyl)-2,4,6-trioxo-hexahydro-
pyrimidin-5-
yloxy]-phenoxy}-benzylamide;
5-(cyclohexyl)-5-[4-(3-fluoro-4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenoxy]-
pyrimidine-
2,4,6-trione;
5-(cyclohexyl)-5-{4-[3-fluoro-4-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-
phenoxy}-
pyrimidine-2,4,6-trione;
1-(4-{4-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-3-propyl-urea; and
Azetidine-1-carboxylic acid 4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-
pyrimidin-
5-yloxy]-phenoxy}-benzylamide;
or pharmaceutically acceptable salts thereof.
The present invention also relates to a pharmaceutical composition for the
treatment of
a condition selected from the group consisting of connective tissue disorders,
inflammatory
disorders, immunology/allergy disorders, infectious diseases, respiratory
diseases,
cardiovascular diseases, eye diseases, metabolic diseases, central nervous
system (CNS)
disorders, liver/kidney diseases, reproductive health disorders, gastric
disorders, skin
SUBSTITUTE SHEET (RULE 26)


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disorders and cancers and other diseases characterized by metalloproteinase
activity in a
mammal, including a human, comprising an amount of a compound of formula I or
a
pharmaceutically acceptable salt thereof effective in such treatments and a
pharmaceutically
acceptable carrier.
The present invention also relates to a pharmaceutical composition for the
inhibition of
matrix metalloproteinases or other metalloproteinases involved in matrix
degradation, in a
mammal, including a human, comprising an effective amount of a compound of
formula I or a
pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a condition
selected from the
group consisting of connective tissue disorders, inflammatory disorders,
immunology/allergy
disorders, infectious diseases, respiratory diseases, cardiovascular diseases,
eye diseases,
metabolic diseases, central nervous system (CNS) disorders, liver/kidney
diseases,
reproductive health disorders, gastric disorders, skin disorders and cancers
and other
diseases characterized by matrix metalloproteinase activity in a mammal,
including a human,
comprising administering to said mammal an amount of a compound of formula 1
or a
pharmaceutically acceptable salt thereof effective in treating such a
condition.
The present invention also relates to a method for the inhibition of matrix
metalloproteinases or other metalloproteinases involved in matrix degradation,
in a mammal,
including a human, comprising administering to said mammal an effective amount
of a
compound of formula I or a pharmaceutically acceptable salt thereof.
The present inventors have also discovered that it is possible to identify
inhibitors of
formula I with differential metalloprotease activity (preferably MMP-13
inhibitory activity). One
group of preferred inhibitors of formula I the inventors have been able to
identify include those
which selectively inhibit MMP-13 preferentially over MMP-1. The compounds of
the invention
also possess selectivity over a related group of enzymes known as reprolysins,
such as TALE
and aggrecanase. Another group of preferred inhibitors of formula I the
inventors have been
able to identify include those which selectively inhibit MMP-13 preferentially
over MMP-1 and
MMP-14. Another group of preferred inhibitors of formula I the inventors have
been able to
identify include those which selectively inhibit MMP-13 preferentially over
MMP-1 and 12.
Another group of preferred inhibitors of formula I the inventors have been
able to identify include
those which selectively inhibit MMP-13 preferentially over MMP-1, 12 and 14.
Another group of
preferred inhibitors of formula I the inventors have been able to identify
include those which
selectively inhibit MMP-13 preferentially over MMP-1, 2, 3, 7, 9 and 14. Most
preferred
compounds of the invention selectively inhibit MMP-13 preferentially over MMP-
1, 2, 3, 7, 9, 12
and 14 and mammalian reprolysins.
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The present invention also relates to a method for treating a medical
condition of the
type that is characterized by the destruction of articular cartilage in a
mammalian subject,
which method comprises administering to the subject having said condition a
therapeutically
effective amount of a suitably substituted pyrimidine-2,4,6-triune, wherein
said suitably
substituted pyrimidine-2,4,6-triune exhibits: i) a MMP-13 ICso of less than
about 100 nM
(more preferably 50nM, most preferably less than 20nM), said MMP-13 ICso
measured by an
recombinant MMP-13 assay, ii) a MMP-1 ICso of greater than about 200 nM (more
preferably
greater than 500nM, most preferably greater than 1~M), said MMP-1 ICso
measured by a
recombinant MMP-1 assay; and iii) a MMP-14 ICso of greater than about 200 nM
(more
preferably greater than 500nM, most preferably greater than 1 pM), said MMP-14
ICso
measured by a recombinant MMP-14 assay.
The present invention also relates to a method for treating the destruction of
articular
cartilage wherein said pyrimidine-2,4,6-triune additionally exhibits a MMP-12
ICso of greater
than about 100 nM (more preferably greater than 200nM, most preferably greater
than
500nM), said MMP-12 ICso measured by a recombinant MMP-12 assay.
The present invention also relates to a method for treating the destruction of
articular
cartilage wherein said pyrimidine-2,4,6-triune additionally exhibits i) a MMP-
2 ICso of greater
than about 200 nM (more preferably greater than 500nM, most preferably greater
than 1 pM),
said MMP-2 ICso measured by a recombinant MMP-2 assay, ii) . a MMP-3 ICso of
greater than
about 200 nM (more preferably greater than 500nM, most preferably greater than
1 pM), said
MMP-3 ICso measured by a recombinant MMP-3 assay, iii) a MMP-7 ICso of greater
than about
200 nM (more preferably greater than 500nM, most preferably greater than 1yM),
said MMP-7
ICso measured by a recombinant MMP-7 assay, and iv) a MMP-9 ICSO of greater
than about
200nM (more preferably greater than 500nM, most preferably greater than 1
ECM), said MMP-9
ICso measured by a recombinant MMP-9 assay.
The term "treating", as used herein, refers to reversing, alleviating,
inhibiting the
progress of, or preventing the disorder or condition to which such term
applies, or one or more
symptoms of such disorder or condition. The term "treatment", as used herein,
refers to the act
of treating, as "treating" is defined immediately above.
"Connective tissue disorders" as used herein refers to disorders such as
degenerative
cartilage loss following traumatic joint injury, osteoarthritis, osteoporosis,
Paget's disease,
loosening of artificial joint implants, periodontal disease and gingivitis.
"Destruction of articular cartilage" as used herein refers to connective
tissue disorders
resulting in articular cartilage destruction, preferably joint injury,
reactive arthritis, acute
SUBSTITUTE SHEET (RULE 26)


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pyrophosphate arthritis (pseudogout), psoriatic arthritis, or juvenile
rheumatoid arthritis, more
preferably osteoarthritis.
"Inflammatory disorders" as used herein refers to disorders such as rheumatoid
arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis,
chondrocalcinosis, gout,
inflammatory bowel disease, ulcerative colitis, Crohn's disease and cachexia.
"Immunology/allergy disorders" as used herein refers to disorders such as
organ
Transplant toxicity, allergic reactions, allergic contact hypersensitivity,
autoimmune disorders
such as those disorders associated with granulomatous inflammation/tissue
remodeling (such
as asthma), immunosuppression and sarcoid.
"Infectious diseases," including those mediated by viruses, bacteria, fungi or
mycobacterial infection, as used herein refers to disorders such as septic
arthritis, AIDS,
fever; Prion diseases, myasthenia gravis, Malaria, sepsis, hemodynamic shock,
and septic
shock.
"Respiratory diseases" as used herein refers to disorders such as
chronic~obstructive
pulmonary disease (including emphysema), acute respiratory distress syndrome,
asthma,
hyperoxic alveolar injury and idiopathic pulmonary fibrosis and other fibrotic
lung diseases.
"Cardiovascular diseases" as used herein refers to disorders such as
atherosclerosis
including atherosclerotic plaque rupture; aortic aneurysm including abdominal
aortic
aneurysm and brain aortic aneurysm; congestive heart failure; myocardial and
cerebral
infarction; stroke; cerebral ischemia; coagulation and acute phase response;
left ventricular
dilation; post ischemic reperfusion injury; angiofibromas; hemangiomas; and
restenosis.
"Eye diseases" as used herein refers to disorders such as aberrant
angiogenesis,
ocular angiogenesis, ocular inflammation, keratoconus, Sjogren's syndrome,
myopia, ocular
tumors, corneal graft rejection, corneal injury, neovascular glaucoma, corneal
ulceration,
corneal scarring, macular degeneration (including "Age Related Macular
Degeneration
(ARMD) including both wet and dry forms), proliferative vitreoretinopathy and
retinopathy of
prematurity.
"Metabolic diseases" as used herein refers to disorders such as diabetes
(including
non-insulin dependent diabetes mellitus, diabetic retinopathy, insulin
resistance, diabetic
ulceration).
"Central Nervous System" (CNS) disorders as used herein refers to disorders
such as
head trauma, spinal cord injury, Inflammatory diseases of the central nervous
system, neuro-
degenerative disorders (acute and chronic), Alzheimer's disease, demyelinating
diseases of
the nervous system, Huntington's disease, Parkinson's disease, peripheral
neuropathy, pain,
cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic
lateral
sclerosis, multiple sclerosis, migraine, depression and anorexia.
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"Liver/Kidney diseases" as used herein refers to disorders such as nephrotic
syndromes such as glomerulonephritis and glomerular disease of the kidney,
proteinuria,
cirrhosis of the liver and interstitial nephritis.
"Reproductive Health disorders" as used herein refers to disorders such as
endometriosis, contraception (male/female), dysmenorrhea, dysfunctional
uterine bleeding,
premature rupture of fetal membranes and abortifactant.
"Gastric disorders" as used herein refers to disorders such as colonic
anastomosis
and gastric ulcers.
"Skin disorders" as used herein refers to disorders such as skin aging,
pressure
sores, psoriasis, eczema, dermatitis, radiation damage, tissue ulceration,
decubital ulcers,
epidermolysis bullosa, abnormal wound healing (topical and oral formulations),
burns and
scleritis.
"Cancers" as used herein refers to disorders such as solid tumor cancer
including
colon cancer, breast cancer, lung cancer and prostrate cancer, tumor invasion,
tumor growth
tumor metastasis, cancers of the oral cavity and pharynx (lip, tongue, mouth,
pharynx),
esophagus, stomach, small intestine, large intestine, rectum, liver and
biliary passages,
pancreas, larynx, lung, bone, connective tissue, skin, cervix uteri, corpus
endometrium, ovary,
testis, bladder, kidney, and other urinary tissues, eye brain and central
nervous system,
thyroid and other endocrine gland, Hodgkin's disease, non-Hodgkin's lymphomas,
multiple
myeloma, and hematopoietic malignancies including leukemias and lymphomas
including
lymphocytic, granulocytic and monocytic.
The subject invention also includes isotopically-labelled compounds, which are
identical to those recited in Formula I, but for the fact that one or more
atoms are replaced by
an atom having an atomic mass or mass number different from the atomic mass or
mass
number usually found in nature. Examples of isotopes that can be incorporated
into
compounds of the invention include isotopes of hydrogen, carbon, nitrogen,
oxygen,
phosphorous, fluorine and chlorine, such as zH, 3H, '3C, '4C, '5N, '80, "O,
3'P, 32P, ssS, ,eF,
and 36C1, respectively. Compounds of the present invention, prodrugs thereof,
and
pharmaceutically acceptable salts of said compounds or of said prodrugs which
contain the
aforementioned isotopes and/or other isotopes of other atoms are within the
scope of this
invention. Certain isotopically-labelled compounds of the present invention,
for example those
into which radioactive isotopes such as 3H and '4C are incorporated, are
useful in drug and/or
substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14,
i.e., '°C, isotopes are
particularly preferred for their ease of preparation and detectability.
Further, substitution with
heavier isotopes such as deuterium, i.e., ZH, can afford certain therapeutic
advantages
resulting from greater metabolic stability, for example increased in vivo half-
life or reduced
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dosage requirements and, hence, may be preferred in some circumstances.
Isotopically-
labelled compounds of Formula I of this invention and prodrugs thereof can
generally be
prepared by carrying out the procedures disclosed in the Schemes and/or in the
Examples
and Preparations below, by substituting a readily available isotopically-
labelled reagent for a
non-isotopically-labelled reagent.
This invention also encompasses pharmaceutical compositions containing
prodrugs of
compounds of the formula I. This invention also encompasses methods of
treating or preventing
disorders that can be treated or prevented by the inhibition of matrix
metalloproteinases or the
inhibition of mammalian reprolysin comprising administering prodrugs of
compounds of the
formula I. Compounds of formula I having free amino, amido, hydroxy,
sulfonamide or carboxylic
groups can be converted into prodrugs. Prodrugs include compounds wherein an
amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or four)
amino acid residues
which are covalently joined through peptide bonds to free amido, amino,
hydroxy or carboxylic
acid groups of compounds of formula I. The amino acid residues include the 20
naturally
occurring amino acids commonly designated by three letter symbols and also
include, 4-
hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine,
norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and
methionine
sulfone. Prodrugs also include compounds wherein carbonates, carbamates,
amides and alkyl
esters, which are covalently, bonded to the above substituents of formula I
through the carbonyl
carbon prodrug sidechain. Prodrugs also include dimers of compounds of formula
I.
One of ordinary skill in the art will appreciate that the compounds of the
invention are
useful in treating a diverse array of diseases. One of ordinary skill in the
art will also
appreciate that when using the compounds of the invention in the treatment of
a specific
disease that the compounds of the invention may be combined with various
existing
therapeutic agents used for that disease.
For the treatment of rheumatoid arthritis, the compounds of the invention may
be
combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal
antibodies
(such as inftiximab, D2E7 and CDP-870) and TNF receptor immunoglobulin
molecules (such
as etanercept), ICE inhibitors, MEKK1 inhibitors, COX-2 inhibitors such as
celecoxib,
rofecoxib, valdecoxib and etoricoxib; low dose methotrexate, lefunimide,
steroids,
glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process
and release
inhibitors, IL-1 receptor antagonists such as Kineret0, CCR-1 antagonists,
hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
The compounds of the invention can also be used in combination with existing
therapeutic agents for the treatment of osteoarthritis. Suitable agents to be
used in
combination include standard non-steroidal anti-inflammatory agents
(hereinafter NSAID's)
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such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen,
fenoprofen,
ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin,
sulindac,
apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-
2 inhibitors
such as celecoxib, valdecoxib, paracoxib, etoricoxib and rofecoxib,
analgesics, steroids,
glucosamines, chondrosamines/ sulfates, gabapentin, A-agonists, IL-1 process
and release
inhibitors, CCR-1 antagonists, LTD-4, LTB-4 and 5-LO inhibitors, p38 kinase
inhibitors and
intraarticular therapies such as corticosteroids and hyaluronic acids such as
hyalgan and
synvisc.
The compounds of the present invention may also be used in combination with
anticancer agents such as endostatin and angiostatin or cytotoxic drugs such
as adriamycin,
daunomycin, cis-platinum, etoposide, paclitaxel, docetaxel and alkaloids, such
as vincristine,
and antimetabolites such as methotrexate.
The compounds of the present invention may also be used in combination with
cardiovascular agents such as calcium channel blockers (such as amlodipine and
nifedipine),
lipid lowering agents such as statins (such as lovastatin, atorvastatin,
pravastatin and
simvastatin), adrenergics such as doxazosin and terazosin; fibrates, beta-
blockers, Ace
inhibitors (such as captopril, lisinopril, fosinopril, enalapril and
quinaprill), Angiotensin-2
receptor antagonists such as losartan and irbesartan; nitrates, CCB's,
diuretics such as
digitalis, and platelet aggregation inhibitors. The compounds of the present
invention may
also be used in combination with plaque rupture preventitive agents such as
statins,
zithromax, NSAIDs including aspirin, heparin, urarfarin, abciximab, TPA and
platelet
Inhibitors. The compounds of the present invention may also be used in
combination with
stroke treatment agents such as NIF, NHEI's and CCRIR antagonists.
The compounds of the present invention may also be used in combination with
CNS
agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs
(such as
deprenyl, carbadopa, L-dopa, dopamine receptor agonists such as ropinirole,
pergolide and
pramipexole; MAOB inhibitors such as selegiline and rasagiline, catechol-O-
methyltrasferase
inhibitors such as tolcapone, A-2 inhibitors, dopamine reuptake inhibitors,
NMDA antagonists,
Nicotine agonists, NK-1 inhibitors, dopamine agonists and inhibitors of
neuronal nitric oxide
synthase), and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2
inhibitors,
propentofylline or metryfonate.
The compounds of the present invention may also be used in combination with
osteoporosis agents such as roloxifene, droloxifene, lasofoxifene or fosomax
and
immunosuppressant agents such as FK-506 and rapamycin.
The compounds of the present invention may also be used in combination with
agents
for the treatment of respiratory diseases such as PDE-IV inhibitors,
steroidals such as
SUBSTITUTE SHEET (RULE 26)


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fluticasone, triamcinolone, budesonide, budesonide and beclomethasone,
anticholinergics
such as ipratropium, sympathomimetics such as salmeterol, albuterol and
Xopenex,
decongestants such as fexofenadine, loratadine, and cetirizine; leukotriene
antagonists such
as zafirlukast and motelukast; and mast cell stabilizers such as zileuton.
The compounds of the present invention may also be used in combination with
agents
for the treatment of skin disorders such as tretinoin, isotretinoin, steroids
such as cortisone
and mometasone, antibiotics such as tetracycline, antifungals such as
clotrimazole,
miconazole and fluconazole and PDE-IV inhibitors.
The compounds of the present invention may also be used in combination with
agents
for the treatment of diabetes such as insulin, including human or humanized
insulin and
inhaled insulin, aldose reductase inhibitors, sorbitol dehydrogenase
inhibitors, antidiabetic
agents such as biguanides such as metformin; glitazones, glycosidase
inhibitors such as
acarbose, sulfonylureas such as glimepiride and glipizide; and
thiazolidinediones such as
pioglitazone, rosiglitazone and trogliazone. Preferred combinations are useful
for treating the
side effects of diabetes such as retinopathy, nephropathy and neuropathy,
preferably
retinopathy.
Detailed Description of the Invention
'The following reaction Scheme illustrates the preparation of the compounds of
the present
invention. Unless otherwise indicated X, Y, Ar', Z, R', Rz and R3 in the
reaction Schemes and
the discussion that follows is defined as above.
SUBSTITUTE SHEET (RULE 26)


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_~8_
SCHEME1
O Ri
L' L3
V
Lz O
X-A-Y- B-G
L ~ IV
La O
O Ri
HEN X-A-Y- B-G
O' 'N O
I
H
SUBSTITUTE SHEET (RULE 26)


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-29-
SCHEME 2
O H O
L, Ls L, Nz
O L2 ~O
VII
VI
O
H
X A-Y- B-G
L
L2 O
VIII
O
H
HEN X-A-Y- B -G
O' 'N O
I
H
IX
O Ri
H~N X-A-Y-B-G
O "N O
I
H
SUBSTITUTE SHEET (RULE 26)


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SCHEME 3
O
H~N
XII
O' 'N O
I
H
O
HEN R1
X
O' 'N O
I
H
1
H R
\N OH
~ XI
O' 'N O
I
H
R1
HEN X A-Y- B-G
O' 'N O
I
H
SUBSTITUTE SHEET (RULE 26)


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SCHEME 4
O
H\N R,
~ X
O "N O
I
H
O R,
R2~N Br
~ XIV
O' _N O
I
R3
O
R
R ~N X A-Y-B-G
O' 'N O
R3
SUBSTITUTE SHEET (RULE 26)


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SCHEME 5
,P
X
XVI I
W
sP
X
A
XVI
B
G
X,
A XV
Y
B
G
SUBSTITUTE SHEET (RULE 26)


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SCHEME 6
O
XIX
Lz O
O
R~
L, ~X.A.Y.B~G XVIii
L2 O
SUBSTITUTE SHEET (RULE 26)


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Scheme 1 refers to the preparation of compounds of the formula I in a two step
synthesis from compounds of the formula V. Referring to Scheme 1, a compound
of the
formula I is prepared from a compound of the formula IV, wherein L' and L2 are
leaving groups
such as methoxy, ethoxy, benzyloxy or chloro, preferably ethoxy, by reaction
with a urea of
the formula III (H2NCONH2) in the presence of a strong base in a polar
solvent. Suitable bases
include sodium methoxide, sodium ethoxide and magnesium methoxide, preferably
sodium
ethoxide. Suitable solvents include alcohols (such as ethanol) or
tetrahydrofuran, preferably
absolute ethanol. The aforesaid reaction is conducted at a temperature of
about 20°C to about
90°C preferably about 50°C to about 65°C for a time
period between about 15 minutes to about
16 hours.
The compound of formula IV is prepared from a compound of formula V, wherein
L3 is a
leaving group such as halo, p-tolylsulfonyloxy (OTs) or methylsulfonyloxy
(OMs), preferably
halo, most preferably chloro or bromo, by reaction with a compound of the
formula II HX-A-Y-B-
G in the presence of a base in a polar solvent. Suitable solvents include
dimethylformamide
(DMF), alcohols (such as ethanol) or tetrahydrofuran, preferably ethanol. The
aforesaid reaction
is conducted at a temperature of about 20°C to about 90°C
preferably about 50°C to about 65°C
for a time period between about 15 minutes to about 16 hours.
The compounds of the formula V can be made by methods well known in the art
such as
those described in PCT Patent Publication WO 98/58925 or reviewed in The
Organic
Chemistry of Drug Synthesis, D. Lednicer and L. A. Mitscher, Volume 1, pages
167 to 277
and references therein. Each of the above referenced publications and
applications is hereby
incorporated by refererice in its entirety.
Compounds of the formula III are commercially available or can be made by
methods
well known to those skilled in the art.
The compounds of formula II, HX-A-Y-B-G, are commercially available or can be
made by methods well known to those skilled in the art or can be made by the
methods of
Scheme 5.
Scheme 2 refers to an alternate preparation of compounds of the formula I in a
three-
step synthesis from compounds of the formula VI or VII. Referring to Scheme 2,
a compound
of the formula I is prepared from a compound of the formula IX by reaction
with a suitable
base and a suitable alkylating agent of the formula R'L4 in the presence of a
solvent. Suitable
bases include sodium hydride, potassium carbonate, sodium carbonate,
triethylamine, pyridine
or triethanolamine; most preferably sodium hydride. Suitable alkylating agents
include those
wherein L° is halo, p-tolylsulfonyloxy (OTs) or methylsulfonyloxy
(OMs), preferably halo, most
preferably chloro or bromo; or alkylating agents include such compounds as
Eshenmoser's
Salts; epoxides or suitably substituted electrophilic aziridines. Suitable
solvents depend upon
SUBSTITUTE SHEET (RULE 26)


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the base used but may be chosen from N,N-dimethylformamide, tetrahydrofuran,
acetonitrile and
water. The aforesaid reaction is conducted at a temperature of about
0°C to about 30°C
preferably about 20°C to about 25°C for a time period between
about 15 minutes to about 16
hours.
A compound of the formula IX may be prepared from a compound of the formula
VIII
by reaction with a urea in the presence of a strong base in a polar solvent.
Suitable bases
include sodium methoxide, sodium ethoxide and magnesium methoxide; preferably
sodium
ethoxide. Suitable solvents include alcohols (such as ethanol) or
tetrahydrofuran, preferably
absolute ethanol. The aforesaid reaction is conducted at a temperature of
about 20°C to about
90°C preferably about 50°C to about 65°C for a time
period between about 15 minutes to about
16 hours.
A compound of the formula VIII may be prepared from a compound of the formula
VI,
wherein L3 is a leaving group such as halo, p-tolylsulfonyloxy (OTs) or
methylsulfonyloxy (OMs),
preferably halo, most preferably chloro, by reaction with a compound of the
formula HX-A-Y-B-
G in the presence of a base in a polar solvent. Suitable bases include sodium
methoxide,
sodium ethoxide, potassium carbonate and sodium hydride; preferably sodium
ethoxide.
Suitable solvents include dimethylformamide (DMF), alcohols (such as ethanol)
or
tetrahydrofuran, preferably ethanol. The aforesaid reaction is conducted at a
temperature of
about 20°C to about 90°C preferably about 50°C to about
70°C for a time period between about
15 minutes to about 16 hours, preferably about 3 hours. Reactions of this type
are further
illustrated by the method of J. B. Niederl and R. T. Roth, J. Amer. Chem.
Soc., 62, 1154 (1940).
Alternatively, a compound of the formula VIII may also be prepared from a
compound of
the formula VII in the presence of a suitable catalyst, preferably
rhodium(II)acetate according to
the procedure described by M. Campbell et al.; Aust. J. Chem., 45, 2061
(1992).
Compounds of the formula VI and VII are commercially available or easily
obtained from
readily available starting materials according to methods well known to those
skilled in the art.
For example compounds of the Formula VII may be prepared according to the
method of D. W.
Peace et al., Synthesis, 658 (1971 ).
Compounds of the formula III are commercially available or can be prepared by
methods well known to those skilled in the art.
Scheme 3 refers to an alternate preparation of compounds of the formula I; in
particular those wherein X is oxygen or -OCHZ-. Referring to Scheme 3, a
compound of the
formula I may be obtained by alkylation of a compound of the formula XI with a
suitable
phenol of the formula HO-A-Y-B-G according to the method of O. Mitsonubu
(Synthesis, 1
(1981 )) or by alkylation with a suitable alkylating agent of the formula
L3CH2A-Y-B-G wherein
L3 is a leaving group such as halo, p-tolylsulfonyloxy (OTs) or
methylsulfonyloxy (OMs),
SUBSTITUTE SHEET (RULE 26)


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preferably halo, most preferably chloro or bromo in a suitable solvent such as
N,N-
dimethylformamide, tetrahydrofuran, acetonitrile in the presence of a suitable
base such as
sodium hydride, potassium carbonate, triethylamine, pyridine or
triethanolamine. The aforesaid
reaction is conducted at a temperature of about 0°C to about
50°C preferably about 20°C for a
time period between about 15 minutes to about 16 hours.
Compounds of the formula XI may be prepared from compounds of the formula X
according to the method of J. A. Vida et al., J. Med. Chem., 17, 732 (1974).
Compounds of the formula X may be prepared from a compound of the formula XII
by
reaction with a suitable base, in the presence of a suitable alkylating agent
of the formula R'L4
and a solvent, such as described in Biehl et al., J.Het.Chem., 23, 9 (1986).
Suitable bases
include sodium hydride, potassium carbonate, triethylamine, pyridine,
triethanolamine; most
preferably triethanolamine. Suitable alkylating agents include those wherein
L4 is halo, p-
tolylsulfonyloxy (OTs) or methylsulfonyloxy (OMs), preferably halo, most
preferably chloro or
bromo; or alkylating agents such as Eshenmoser's Salt; epoxides or suitably
substituted
electrophilic aziridines. Suitable solvents depend upon the base used but may
be chosen from
N,N-dimethylformamide, tetrahydrofuran, acetonitrile and water. The aforesaid
reaction is
conducted at a temperature of about 0°C to about 30°C preferably
about 20°C to about 25°C for
a time period between about 15 minutes to about 16 hours.
Compounds of the formula XII are commercially available or can be easily
prepared by
those skilled in the art according to the methods reviewed in The Organic
Chemistry of Drug
Synthesis, D. Lednicer and L. A. Mitscher, Volume 1, pages 167 to 277 and
references cited
therein.
Scheme 4 refers to an alternate preparation of compounds of the formula I.
Referring
to Soheme 4, a compound of the formula I may be obtained by alkylation of the
compound of
formula XIV with a compound of the formula HX-A-Y-B-G in the presence of a
base. Suitable
bases include polymer bound bases such as 1,5,7-trazabicyclo[4.4.0)dec-5-ene
bound to
polystyrene (PTBD) crosslinked with 2% divinyl benzene (DVB) or alkali metal
carbonates,
preferably PTBD. Suitable solvents include alcohols (such as ethanol, methanol
and butanol),
DMF, THF or acetonitrile, preferably absolute acetonitrile. The aforesaid
reaction is conducted
at a temperature of about 20°C to about 90°C preferably about
50°C to about 65°C for a time
period between about 15 minutes to about 16 hours.
The compound of formula XIV is prepared from a compound of formula X by
reaction
with a suitable bromination reagent such as Br2 or Br2 Ph3P. The brominaton
may be carried
out in a reaction inert solvent such as water (in the presence of a suitable
base), acetic acid,
acetonitrile or DMF, preferably water. The aforesaid reaction is conducted at
a temperature of
SUBSTITUTE SHEET (RULE 26)


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about 0°C to about 40°C preferably about 20°C to about
35°C for a time period between about
15 minutes to about 16 hours.
Alternatively, compounds of the formula I wherein X is sulfur or -SCHZ , or
their
oxidized derivatives >S02, >S0, -SOzCH2-, -SOCHz-, can be prepared by reacting
a
pyrimidine-2,4,6-trione ring of a compound of the formula X with a suitable
disulfide of the
formulae (SA-Y-B-G)2 or (SCH2A-Y-B-G)z in a suitable solvent such as N,N-
dimethylformamide,
tetrahydrofuran, acetonitrile in the presence of a suitable base, such as
sodium hydride,
potassium carbonate, triethylamine, pyridine or triethanolamine. The aforesaid
reaction is
conducted at a temperature of about 20°C to about 70°C
preferably about 20°C for a time period
between about 15 minutes to about 16 hours.
Disulfides (SA-Y-B-G)z or (SCHzA-Y-B-G)z may be prepared from the
corresponding
thiols HSA-Y-B-G or HSCHzA-Y-B-G by oxidative methods well known to those
skilled the art.
Compounds of the formula X are commercially available, or the methods of
scheme 3
or can be made by methods well known to those skilled in the art.
One skilled in the art will also appreciate that the side chains denoted R'
and X-A-Y-
B-G may be added as a unit, as is discussed above, or can be added as separate
modules
such as X-A followed by the addition of a second unit L'-Y-B-G. Such methods
are well
known to those skilled in the art.
Scheme 5 describes the preparation of intermediates of the formula XV.
Intermediates of the formula XV are used to prepare compounds of formula I in
Schemes 1-4.
Referring to Scheme 5, compounds of the formula XV, wherein X' is >(C=O)-CI,
OH, SH,
>NHR'°, CHZOH, CHZSH, CHZNHR'° and S02NHR'°, may be
prepared from the appropriate
compound of formula XVI by deprotection under conditions commonly known to
those of
ordinary skill in the art and referenced in Greene and Wuts, "Protecting
Groups in Organic
Synthesis," (John Wiley & Son Press, 2nd Ed). Compounds of the formula XV,
wherein X' is
-(C=O)-CI can be prepared from compounds of the formula XVI, wherein P is
hydroxy, by
reaction with chlorinating agents such as thionyl chloride or phosphorous
oxychloride.
Compounds of the formula XVI, wherein Y is O, S, CH20, CHZS, NR'e, CH~NR'8 or
SOZNR'e, can be prepared by treatment of a compound of formula XVII, wherein W
is Br or I,
by reaction with a compound of the formula G-Z-YH in the presence of a
suitable base, such
as an alkali metal carbonate or hydroxide base, preferably potassium
carbonate, in the
presence of a suitable catalyst, such as a copper (0) catalyst, preferably
finely powdered
copper bronze in a polar aprotic solvent, such as DMF or NMP at a temperature
between
about 80°C and 140°C for about 6 to 24 hours. Alternatively,
coupling may be carried out
under Buchwald and Hartwig's conditions in cases, wherein W is CI, Br, I or
trifalte (Tf0),
using a suitable base, such as an alkoxide base, preferably sodium tent-
butoxide in a suitable
SUBSTITUTE SHEET (RULE 26)


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solvent, such as an ethereal solvent, preferably dioxane, in the presence of a
palladium (0)
catalyst, such as Pd2(dba)3 and a suitable ligand, such as a triaryl phosphine
ligand,
preferably tri(ortho-tolyl)phosphine at a temperature of about 40°C to
100°C for about 1 to 48
hours. Such conditions are reviewed in Angew. Chem. Int. Ed. Engl. 1998, 37,
2046-2067
and are well known to those of ordinary skill in the art. Alternatively,
coupling may be carried
out in cases where W is B(OH)z using a copper catalyst, preferably copper (II)
acetate in the
presence of 4 angstrom molecular sieves and a suitable tertiary amine base,
such as
triethylamine or pyridine, in a suitable solvent, such as methylene chloride,
DMSO or THF,
under an atmosphere of oxygen gas at a temperature of about 10°C to
50°C, preferably about
23°C for about 6 to 72 hours. In certain cases (e.g. where Y is CHzO,
CHzS, CHZNR'e or
SOZNR'8), it may be advantageous to use a compound of formula XVII, wherein X
is CHO and
W is F, for the conversion to compound XVI by treatment with a compound of
formula G-Z-YH
in the presence of a suitable base, such as an alkali metal hydride base,
preferably sodium
hydride, in a polar aprotic solvent, such as DMF or THF, at a temperature of
0°C to 140°C for
1 to 24 hours. Such compounds can be converted into compounds of the formula
XVI,
wherein X is O, by so-called Bayer Villager oxidation conditions or to
compounds of formula.
XVI, wherein X is NR'e, by the so-called Curtius rearrangement, both of which
are classical
organic transformations and well known to those of ordinary skill in the art.
Compounds of the formula XVI, wherein Y is >S02, >S=0, -CHzSO-, -CH2S02-,
SO(CHz)"-, -SOZ(CHz)~ , may be prepared from the corresponding lower oxidation
state
compounds (e.g. wherein Y is -S-, -CHzS-, -S-(CHz)~-) by oxidation with a
suitable oxidant,
such as a peroxy acid, preferably peracetic acid, or an organic peroxide,
preferably m-
chloroperoxybenzoic acid or tert-butyl hydroperoxide, in a suitable solvent,
such as methylene
chloride or t-butanol, at a temperature between about -10°C and
30°C for 1 to 8 hours.
Compounds of the formula XVI, wherein Y is O(CHZ)~, S(CHz)~. NR'e(CHZ)~ can be
prepared from compounds of the formula XVII, wherein W is L-(CHz)"-, wherein L
is halo,
mesyloxy (Ms0) or tosyloxy (Ts0), by treatment with the appropriate compound
of the formula
G-Z-Y-H, wherein Y is O, S or NR'e, by treatment with a suitable base, such as
an alkali metal
carbonate base, preferably potassium carbonate or cesium carbonate, in the
presence of a
polar aprotic solvent, such as DMF or THF at a temperature between about
23°C and 80°C,
preferably 20 to 50°C for 1 to 24 hours.
Compounds of the formula XVI, wherein Y is >C=0 or CH=CH, can be prepared by
treatment of a compound of formula XVII, wherein W is -B(OH)2, -ZnX or -SnR3,
with a
compound of the formula G-Z-Y-X, wherein X is halo, preferably CI,Br or I, in
the presence of
a palladium or nickel catalyst, preferably Pd(PPh3)~, in a suitable solvent,
such as toluene,
THF, DMF or DMSO at a temperature between 23 °C and 110°C for a
period of 1 to 24 hours.
SUBSTITUTE SHEET (RULE 26)


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Such reactions may be facilitated by the presence of a copper salt, such as
cuprous iodide or
cuprous bromide. Compounds of the formula XVI, wherein Y is -C--__C- can be
prepared by
treatment of a compound of formula XVII, wherein W is halo or triflate,
preferably Br or I, with
a compound of the formula G-Z-Y-H, in the presence of a suitable base, such as
a
trialkylamine base, preferably triethylamine and a palladium catalyst,
preferably Pd(PPh3)4 in a
suitable solvent, such as THF or DMF at a temperature between 23 and
60°C for a period of 1
to 24 hours. One of ordinary skill in the art will recognize that compounds of
the formula XVI,
wherein Y is -CHZ(CHZ)~-, can be prepared by reduction of the aforementioned
compounds,
wherein Y is -CH=CH- or -C=C-, by reduction under a hydrogen atmosphere at
ambient
pressure to 50 psi in the presence of a palladium catalyst, preferably
palladium on charcoal, in
a suitable solvent, such as methanol or ethyl acetate, at a temperature
between about 20°C
and 50°C for about 1 to 24 hours.
Compounds of the formula I, where P is a suitable protecting group as defined
in
Green and Wuts, supra, are either commercially available, known, or may be
prepared from
commercially available starting materials by methods known to those of
ordinary skill in the
art.
Scheme 6 describes the preparation of compounds of the formula XVIII, wherein
X is
-OCH~-, SCHZ or -N(R'°)CHz . Compounds of the formula XVIII are
compounds of formula IV
in Scheme 1, wherein R' is hydrogen. Referring to Scheme 6, compounds of
formula XVIII
can be prepared by treatment of a compound of formula XIX with a compound of
formula G-B-
Y-A-XH, wherein X is O, S or NR'°, in the presence of a suitable base,
such as an alkali metal
hydride base, preferable sodium hydride, and a suitable solvent, such as an
alcoholic solvent,
THF or DMF at a temperature of about -20 to 50°C, preferably about
0°C to 23°C for about 1
to 24 hours.
The compounds of the formula I, which are basic in nature, are capable of
forming a
wide variety of different salts with various inorganic and organic acids.
Although such salts
must be pharmaceutically acceptable for administration to animals, it is often
desirable in
practice to initially isolate a compound of the formula 1 from the reaction
mixture as a
pharmaceutically unacceptable salt and then simply convert the latter back to
the free base
compound by treatment with an alkaline reagent, and subsequently convert the
free base to a
pharmaceutically acceptable acid addition salt. The acid addition salts of the
base
compounds of this invention are readily prepared by treating the base compound
with a
substantially equivalent amount of the chosen mineral or organic acid in an
aqueous solvent
medium or in a suitable organic solvent such as methanol or ethanol. Upon
careful
evaporation of the solvent, the desired solid salt is obtained.
SUBSTITUTE SHEET (RULE 26)


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The acids which are used to prepare the pharmaceutically acceptable acid
addition
salts of the base compounds of this invention are those which form non-toxic
acid addition
salts, i.e., salts containing pharmacologically acceptable anions, such as
hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid
phosphate, acetate,
lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate,
saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-
(2-hydroxy-3-
naphthoate)] salts.
Those compounds of the formula I which are also acidic in nature, are capable
of
forming base salts with various pharmacologically acceptable cations. Examples
of such salts
include the alkali metal or alkaline-earth metal salts and particularly, the
sodium and
potassium salts. These salts are all prepared by conventional techniques. The
chemical
bases which are used as reagents to prepare the pharmaceutically acceptable
base salts of
this invention are those which form non-toxic base salts with the herein
described acidic
compounds of formula I. These non-toxic base salts include those derived from
such
pharmacologically acceptable cations as sodium, potassium, calcium and
magnesium, etc.
These salts can easily be prepared by treating the corresponding acidic
compounds with an
aqueous solution containing the desired pharmacologically acceptable cations,
and then
evaporating the resulting solution to dryness, preferably under reduced
pressure.
Alternatively, they may also be prepared by mixing lower alkanolic solutions
of the
acidic compounds and the desired alkali metal alkoxide together, and then
evaporating the
resulting solution to dryness in the same manner as before. In either case,
stoichiometric
quantities of reagents are preferably employed in order to ensure completeness
of reaction
and maximum product yields.
BIOLOGICAL ASSAYS
The ability of the compounds of formula I or their pharmaceutically acceptable
salts
(hereinafter also referred to as the compounds of the present invention) to
inhibit
metalloproteinases or mammalian reprolysins and, consequently, demonstrate
their
effectiveness for treating diseases characterized by metalloproteinase
activity is shown by the
following in vitro and in vivo assay tests.
MMP Assays
MMP-13 selective inhibitors can be identified by screening the inhibitors of
the present
invention through the MMP fluorescence assays described below and selecting
those agents
with MMP-13/MMP-X inhibition ICso ratios of 100 or greater and potency of less
than 100 nM,
where MMP-X refers to one or more other MMP's.
Non-selective collagenase inhibitors as used herein, unless otherwise
mentioned, refer
to agents which exhibit less than a 100 fold selectivity for the inhibition of
MMP-13 enzyme
SUBSTITUTE SHEET (RULE 26)


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activity over MMP-X enzyme activity or a potency of more than 100nM as defined
by the ICso
results from the MMP-13/MMP-X fluorescence assays described below.
The ability of collagenase inhibitors to inhibit collagenase activity is well
known in the
art. The degree of inhibition of a particular MMP for several compounds has
been well
documented in the art and those skilled in the art will know how to normalize
different assay
results to those assays reported herein. The following assays may be used to
identify matrix
metalloproteinase inhibitors.
Inhibition of Human Collagenase (MMP-1)
Human recombinant collagenase is activated with trypsin. The amount of trypsin
is
optimized for each lot of collagenase-1 but a typical reaction uses the
following ratio: 5 pg
trypsin per 100 pg of c011agenase. The trypsin and collagenase are incubated
at room
temperature for 10 minutes then a five fold excess (50 mg/10 mg trypsin) of
soybean trypsin
inhibitor is added.
Stock solutions (10 mM) of inhibitors are made up in dimethylsulfoxide and
then diluted
using the following scheme:
10 mM ------> 120 pM ------> 12 ~M ------> 1.2 pM ------> 0.12 ~M
Twenty-five microliters of each concentration is then added in triplicate to
appropriate wells of
a 96 well microfluor plate. The final concentration of inhibitor will be a 1:4
dilution after
addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are
set up in wells
D7-D12 and negative controls (no enzyme, no inhibitors) are set in wells D1-
D6.
Collagenase-1 is diluted to 240 ng/ml and 25 t~l is then added to appropriate
wells of the
microtluor plate. Final concentration of collagenase in the assay is 60 ng/ml.
Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NHz) is made as a 5 mM
stock in dimethylsulfoxide and then diluted to 20 pM in assay buffer. The
assay is initiated by
the addition of 50 p1 substrate per well of the microfluor plate to give a
final concentration of 10
pM.
Fluorescence readings (360 nM excitation, 460 nm emission) are taken at time 0
and
then at 20 minute intervals. The assay is conducted at room temperature with a
typical assay
time of 3 hours
Fluorescence versus time is then plotted for both the blank and collagenase
containing
samples (data from triplicate determinations is averaged). A time point that
provides a good
signal (at least five fold over the blank) and that is on a linear part of the
curve (usually around
120 minutes) is chosen to determine ICso values. The zero time is used as a
blank for each
compound at each concentration and these values are subtracted from the 120
minute data.
Data is plotted as inhibitor concentration versus % control (inhibitor
fluorescence divided by
SUBSTITUTE SHEET (RULE 26)


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fluorescence of collagenase alone x 100). ICso's are determined from the
concentration of
inhibitor that gives a signal that is 50% of the control.
If ICso's are reported to be less than 0.03 ~M then the inhibitors are assayed
at
concentrations of 0.3 ~M, 0.03 ECM, and 0.003 pM.
Inhibition of Gelatinise (MMP-2)
Human recombinant 72 kD gelatinise (MMP-2, gelatinise A) is activated for 16-
18
hours with 1 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM
stock in
0.2 N NaOH) at 4°C, rocking gently.
mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
10 buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCl2. 20 pM ZnClz and 0.02%
BRIJ-35
(vol./vol.)) using the following scheme:
10 mM--~ 120 yM----~ 12 pM-----~ 1.2 pM----~ 0.12 ~M
Further dilutions are made as necessary following this same scheme. A minimum
of four
inhibitor concentrations for each compound are performed in each assay. 25 ESL
of each
concentration is then added to triplicate wells of a black 96 well U-bottomed
microfluor plate.
As the final assay volume is 100 EiL, final concentrations of inhibitor are
the result of a further
1:4 dilution (i.e. 30 yM ---~ 3 ~M ----~ 0.3 yM ---~ 0.03 yM, etc.). A blank
(no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 yL per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 25 ng/mL
(0.34 nM).
A flue mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-
Dpa-
Ala-Arg-NHz) is diluted in assay buffer to 20 pM. The assay is initiated by
addition of 50 ~L of
diluted substrate yielding a final assay concentration of 10 ~M substrate. At
time zero,
fluorescence reading (320 excitation; 390 emission) is immediately taken and
subsequent
readings are taken every fifteen minutes at room temperature with a PerSeptive
Biosystems
CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICso
determinations. The zero
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
versus percent of enzyme control. ICso's are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
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Inhibition of Stromelysin Activity (MMP-3)
Human recombinant stromelysin (MMP-3, stromelysin-1 ) is activated for 20-22
hours
with 2 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock
in 0.2 N
NaOH) at 37°C.
10 mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
buffer (50 mM TRIS, pH 7.5, 150 mM NaCI, 10 mM CaCh and 0.05% BRIJ-35
(vol./vol.)) using
the following scheme:
mM--~ 120 ~M---~ 12 pM-----~ 1.2 pM---~ 0.12 ~M
Further dilutions are made as necessary following this same scheme. A minimum
of four
10 inhibitor concentrations for each compound are performed in each assay. 25
yL of each
concentration is then added to triplicate wells of a black 96 well U-bottomed
microfluor plate.
As the final assay volume is 100 EiL, final concentrations of inhibitor are
the result of a further
1:4 dilution (i.e. 30 ~M -----~ 3 yM ---~ 0.3 pM ---~ 0.03 ~M, etc.). A blank
(no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 200 ng/mL in assay buffer, 25 ~.L per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 50 ng/mL
(0.875 nM).
A ten mM dimethylsulfoxide stock solution of substrate (Mca-Arg-Pro-Lys-Pro-
Val
Glu-Nva-Trp-Arg-Lys(Dnp)-NHZ) is diluted in assay buffer to 6 ~M. The assay is
initiated by
addition of 50 ESL of diluted substrate yielding a final assay concentration
of 3 ECM substrate.
At time zero, fluorescence reading (320 excitation; 390 emission) is
immediately taken and
subsequent readings are taken every fifteen minutes at room temperature with a
PerSeptive
Biosystems CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICso
determinations. The zero
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
versus percent of enzyme control. ICso's are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
SUBSTITUTE SHEET (RULE 26)


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Inhibition of Human 92 kD Gelatinise (MMP
Inhibition of 92 kD gelatinise (MMP-9) activity is assayed using the Mca-Pro-
Leu-Gly-
Leu-Dpa-Ala-Arg-NH2 substrate (10 EiM) under similar conditions as described
above for the
inhibition of human collagenase (MMP-1 ).
Human recombinant 92 kD gelatinise (MMP-9, gelatinise B) is activated for 2
hours
with 1 mM p-aminophenyl-mercuric acetate (from a freshly prepared 100 mM stock
in 0.2 N
NaOH) at 37 C.
mM dimethylsulfoxide stock solutions of inhibitors are diluted serially in
assay
buffer (50 mM TRIS, pH 7.5, 200 mM NaCI, 5 mM CaCl2, 20 ~M ZnCl2, 0.02% BRIJ-
35
10 (vol./vol.)) using the following scheme:
10 mM----~ 120 yM---~ 12 yM---~ 1.2 ~M-----~ 0.12 pM
Further dilutions are made as necessary following this same scheme. A minimum
of
four inhibitor concentrations for each compound are performed in each assay.
25 pL of each
concentration is then added to triplicate wells of a black 96 well U-bottomed
microfluor plate.
As the final assay volume is 100 pL, final concentrations of inhibitor are the
result of a further
1:4 dilution (i.e. 30 ~M ----~ 3 pM ----~ 0.3 pM ---~ 0.03 ~M, etc.). A blank
(no enzyme, no
inhibitor) and a positive enzyme control (with enzyme, no inhibitor) are also
prepared in
triplicate.
Activated enzyme is diluted to 100 ng/mL in assay buffer, 25 ~L per well is
added to
appropriate wells of the microplate. Final enzyme concentration in the assay
is 25 ng/mL
(0.27 nM).
A five mM dimethylsulfoxide stock solution of substrate (Mca-Pro-Leu-Gly-Leu-
Dpa-
Ala-Arg-NH2) is diluted in assay buffer to 20 yM. The assay is initiated by
addition of 50 yL of
diluted substrate yielding a final assay concentration of 10 pM substrate. A 0
time
fluorescence reading (320 excitation; 390 emission) is immediately taken and
subsequent
readings are taken every fifteen minutes at room temperature with a PerSeptive
Biosystems
CytoFluor Multi-Well Plate Reader with the gain at 90 units.
The average value of fluorescence of the enzyme and blank are plotted versus
time.
An early time point on the linear part of this curve is chosen for ICSp
determinations. The 0
time point for each compound at each dilution is subtracted from the latter
time point and the
data then expressed as percent of enzyme control (inhibitor fluorescence
divided by
fluorescence of positive enzyme control x 100). Data is plotted as inhibitor
concentration
versus percent of enzyme control. ICSp's are defined as the concentration of
inhibitor that
gives a signal that is 50% of the positive enzyme control.
Inhibition of MMP-13
SUBSTITUTE SHEET (RULE 26)


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Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenyl mercuric
acetate) for 1.5 hours, at 37°C and is diluted to 400 mg/ml in assay
buffer (50 mM Tris, pH 7.5,
200 mM sodium chloride, 5 mM calcium chloride, 20 pM zinc chloride, 0.02%
brij). Twenty-five
microliters of diluted enzyme is added per well of a 96 well microfluor plate.
The enzyme is then
diluted in a 1:4 ratio in the assay by the addition of inhibitor and substrate
to give a final
concentration in the assay of 100 mg/ml.
mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then
diluted in
assay buffer as per the inhibitor dilution scheme for inhibition of human
collagenase (MMP-1 ):
Twenty-five microliters of each concentration is added in triplicate to the
microfluor plate. The
10 final concentrations in the assay are 30 ~M, 3 pM, 0.3 pM, and 0.03 ~M.
Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NHZ) is prepared as for
inhibition of human collagenase (MMP-1 ) and 50 p1 is added to each well to
give a final assay
concentration of 10 pM. Fluorescence readings (360 nM excitation; 450
emission) are taken at
time 0 and every 5 minutes for 1 hour.
Positive controls consist of enzyme and substrate with no inhibitor and blanks
consist of
substrate only.
ICS°'s are determined as per inhibition of human collagenase (MMP-1).
If ICS°'s are
reported to be less than 0.03 pM, inhibitors are then assayed at final
concentrations of 0.3 yM,
0.03 pM, 0.003 pM and 0.0003 pM.
Collagen film MMP-13 Assay
Rat type I collagen is radiolabeled with '4C acetic anhydride (T.E. Cawston
and A.J.
Barrett, Anal. Biochem., 99, 340-345 (1979)) and used to prepare 96 well
plates containing
radiolabeled collagen films (Barbara Johnson-Wint, Anal. Biochem., 104, 175-
181 (1980)).
When a solution containing collagenase is added to the well, the enzyme
cleaves the
insoluble collagen which unwinds and is thus solubilized. Collagenase activity
is directly
proportional to the amount of collagen solubilized, determined by the
proportion of
radioactivity released into the supernatant as measured in a standard
scintillation counter.
Collagenase inhibitors are, therefore, compounds which reduce the radioactive
counts
released with respect to the controls with no inhibitor present. One specific
embodiment of
this assay is described in detail below.
For determining the selectivity of compounds for MMP-13 versus MMP-1 using
collagen as a substrate, the following procedure is used. Recombinant human
proMMP-13 or
proMMP-1 is activated according to the procedures outlined above. The
activated MMP-13 or
MMP-1 is diluted to 0.6 ug/ml with buffer ( 50 mM Tris pH 7.5, 150 mM NaCI, 10
mM CaCl2 , 1
uM ZnClz, 0.05% Brij-35, 0.02% sodium azide).
SUBSTITUTE SHEET (RULE 26)


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Stock solutions of test compound (10mM) in dimethylsulfoxide are prepared.
Dilutions of the test compounds in the Tris buffer, above, are made to 0.2,
2.0, 20, 200, 2000
and 20000 nM.
100 y1 of appropriate drug dilution and 100 y1 of diluted enzyme are pipetted
into wells
of a 96 well plate containing collagen films labeled with '4C-collagen. The
final enzyme
concentration is 0.3 ug/ml while the final drug concentration is 0.1, 1.0, 10,
100, 1000 nM.
Each drug concentration and control is analyzed in triplicate. Triplicate
controls are also run
for the conditions in which no enzyme is present and for enzyme in the absence
of any
compound.
The plates are incubated at 37°C for a time period such that around 30 -
50% of the
available collagen is solubilized - determined by counting additional control
wells at various
time points. In most cases around 9 hours of incubation are required. When the
assay has
progressed sufficiently, the supernatant from each well is removed and counted
in a
scintillation counter. The background counts (determined by the counts in the
wells with no
enzyme) are subtracted from each sample and the % release calculated in
relation to the
wells with enzyme only and no inhibitor. The triplicate values for each point
are averaged and
the data graphed as percent release versus drug concentration. IC5°'s
are determined from
the point at which 50% inhibition of release of radiolabeled collagen is
obtained.
To determine the identity of the active collagenases in cartilage conditioned
medium,
assays were carried out using collagen as a substrate, cartilage conditioned
medium
containing collagenase activity and inhibitors of varying selectivity. The
cartilage conditioned
medium was collected during the time at which collagen degradation was
occurring and thus
is representative of the collagenases responsible for the collagen breakdown.
Assays were
carried out as outlined above except that instead of using recombinant MMP-13
or
recombinant MMP-1, cartilage conditioned medium was the enzyme source.
IL-1 Induced Cartilage Collagen Degradation From Bovine Nasal Cartilage
This assay uses bovine nasal cartilage explants which are commonly used to
test the
efficacy of various compounds to inhibit either IL-1 induced proteoglycan
degradation or IL-1
induced collagen degradation. Bovine nasal cartilage is a tissue that is very
similar to articular
cartilage, i.e. chondrocytes surrounded by a matrix that is primarily type II
collagen and
aggrecan. The tissue is used because it: (1 ) is very similar to articular
cartilage, (2) is readily
available, (3) is relatively homogeneous, and (4) degrades with predictable
kinetics after IL-1
stimulation.
Two variations of this assay have been used to assay compounds. Both
variations
give similar data. The two variations are described below:
Variation 1
SUBSTITUTE SHEET (RULE 26)


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Three plugs of bovine nasal cartilage (approximately 2 mm diameter x 1.5 mm
long)
are placed into each well of a 24 well tissue culture plate. One ml of
serumless medium is
then added to each well. Compounds are prepared as 10 mM stock solutions in
DMSO and
then diluted appropriately in serumless medium to final concentrations, e.g.,
50, 500 and 5000
nM. Each concentration is assayed in triplicate.
Human recombinant IL-1a (5ng/mL) (IL-1) is added to triplicate control wells
and to
each well containing drug. Triplicate control wells are also set up in which
neither drug nor IL-
1 are added. The medium is removed and fresh medium containing IL-1 and the
appropriate
drug concentrations is added on days 6, 12, 18 and 24 or every 3 - 4 days if
necessary. The
media removed at each time point is stored at -20°C for later analysis.
When the cartilage in
the IL-1 alone wells has almost completely resorbed (about day 21 ), the
experiment is
terminated. The medium, is removed and stored. Aliquots (100 u1) from each
well at each
time point are pooled, digested with papain and then analyzed for
hydroxyproline content.
Background hydroxyproline (average of wells with no IL-1 and no drug) is
subtracted from
each data point and the average calculated for each triplicate. The data is
then expressed as
a percent of the IL-1 alone average value and plotted. The ICso is determined
from this plot.
Variation 2
The experimental set-up is the same as outlined above in Variation 1, until
day 12.
On day 12, the conditioned medium from each well is removed and frozen. Then
one ml of
phosphate buffered saline (PBS) containing 0.5 pg/ml trypsin is added to each
well and
incubation continued for a further 48 hours at 37°C. After 48 hours
incubation in trypsin, the
PBS solution is removed. Aliquots (50 p1) of the PBS/trypsin solution and the
previous two
time points (days 6 and 12) are pooled, hydrolyzed and hydroxyproline content
determined.
Background hydroxyproline (average of wells with no IL-1 and no drug) is
subtracted from
each data point and the average calculated for each triplicate. The data is
then expressed as
a percent of the IL-1 alone average value and plotted. The ICso is determined
from this plot.
In this variation, the time course of the experiment is shortened
considerably. The addition of
trypsin for 48 hours after 12 days of IL-1 stimulation likely releases any
type II collagen that
has been damaged by collagenase activity but not yet released from the
cartilage matrix. In
the absence of IL-1 stimulation, trypsin treatment produces only low
background levels of
collagen degradation in the cartilage explants.
Inhibition of TNF Production
The ability or inability of the compounds or the pharmaceutically acceptable
salts thereof
to inhibit the production of TNF is shown by the following in vitro assay:
Human Monocyte Assay
Human mononuclear cells were isolated from anti-coagulated human blood using a
one-
SUBSTITUTE SHEET (RULE 26)


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step Ficoll-hypaque separation technique. (2) The mononuclear cells were
washed three times
in Hanks balanced salt solution (HBSS) with divalent canons and resuspended to
a density of 2
x 106 /ml in HBSS containing 1 % BSA. Differential counts determined using the
Abbott Cell Dyn
3500 analyzer indicated that rnonocytes ranged from 17 to 24% of the total
cells in these
preparations.
180 p1 of the cell suspension was aliquoted into flat bottom 96 well plates
(Costar).
Additions of compounds and LPS (100 ng/ml final concentration) gave a final
volume of 200 y1.
All conditions were performed in triplicate. After a four hour incubation at
37°C in an humidified
COZ incubator, plates were removed and centrifuged (10 minutes at
approximately 250 x g) and
the supernatants removed and assayed for TNF a using the R&D ELISA Kit.
Aggrecanase Assay
Primary porcine chondrocytes from articular joint cartilage are isolated by
sequential
trypsin and collagenase digestion followed by collagenase digestion overnight
and are plated
at 2 X 105 cells per well into 48 well plates with 5 E~Ci / ml 35S (1000
Ci/mmol) sulphur in type I
collagen coated plates. Cells are allowed to incorporate label into their
proteoglycan matrix
(approximately 1 week) at 37°C, under an atmosphere of 5% CO~.
The night before initiating the assay, chondrocyte monolayers are washed two
times
in DMEM/ 1 % PSF/G and then allowed to incubate in fresh DMEM /1 % FBS
overnight.
The following morning chondrocytes are washed once in DMEM/1%PSF/G. The final
wash is allowed to sit on the plates in the incubator while making dilutions.
Media and dilutions can be made as described in the Table below.
Control Media DMEM alone (control media)


IL-1 Media DMEM + IL-1 (5 ng/ml)


Drug Dilutions Make all compounds stocks at 10 mM in DMSO.


Make a 100 uM stock of each compound in
DMEM in 96 well


plate. Store in freezer overnight.


The next day perform serial dilutions in
DMEM with IL-1 to 5 uM,


500 nM, and 50 nM.


Aspirate final wash from wells and add
50 u1 of compound from


above dilutions to 450 u1 of IL-1 media
in appropriate wells of the


48 well plates.


Final compound concentrations equal 500
nM, 50 nM, and 5 nM.


All samples completed in triplicate with
Control and IL-1 alone


samples on each plate.


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Plates are labeled and only the interior 24 wells of the plate are used. On
one of the
plates, several columns are designated as IL-1 (no drug) and Control (no IL-1,
no drug).
These control columns are periodically counted to monitor 35S-proteoglycan
release. Control
and IL-1 media are added to wells (450 u1) followed by compound (50 u1) so as
to initiate the
assay. Plates are incubated at 37°C, with a 5% COZ atmosphere.
At 40-50 % release (when CPM from IL-1 media is 4-5 times control media) as
assessed by liquid scintillation counting (LSC) of media samples, the assay is
terminated (9-
12 hours). Media is removed from all wells and placed in scintillation tubes.
Scintillate is
added and radioactive counts are acquired (LSC). To solubilize cell layers,
500 u1 of papain
digestion buffer (0.2 M Tris, pH 7.0, 5 mM EDTA, 5 mM DTT, and 1 mg/ml papain)
is added to
each well. Plates with digestion solution are incubated at 60°C
overnight. The cell layer is
removed from the plates the next day and placed in scintillation tubes.
Scintillate is then
added, and samples counted (LSC).
The percent of released counts from the total present in each well is
determined.
Averages of the triplicates are made with control background subtracted from
each well. The
percent of compound inhibition is based on IL-1 samples as 0% inhibition (100%
of total
counts).
The compounds of the present invention that were tested all have ICso's in at
least
one of the above assays of less than 100 pM preferably less than 100nM.
Certain preferred
groups of compounds possess differential selectivity toward the various MMP's
or ADAMs.
One group of preferred compounds possess selective activity towards MMP-13
over MMP-1.
Another preferred group of compounds possess selective activity towards MMP-13
over
MMP-1 and MMP-12.
For administration to mammals, including humans, for the inhibition of matrix
metalloproteinases or mammalian reprolysin, a variety of conventional routes
may be used
including oral, parenteral (e.~c., intravenous, intramuscular or
subcutaneous), buccal, anal and
topical. In general, the compounds of the invention (hereinafter also known as
the active
compounds) will be administered at dosages betvveen about 0.1 and 25 mg/kg
body weight of
the subject to be treated per day, preferably from about 0.3 to 5 mg/kg.
Preferably the active
compound will be administered orally or parenterally. However, some variation
in dosage will
necessarily occur depending on the condition of the subject being treated. The
person
responsible for administration will, in any event, determine the appropriate
dose for the individual
subject.
The compounds of the present invention can be administered in a wide variety
of
different dosage forms, in general, the therapeutically effective compounds of
this invention are
SUBSTITUTE SHEET (RULE 26)


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present in such dosage forms at concentration levels ranging from about 5.0%
to about 70% by
weight.
For oral administration, tablets containing various excipients such as
microcrystalline
cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine
may be employed
along with various disintegrants such as starch (and preferably corn, potato
or tapioca starch),
alginic acid and certain complex silicates, together with granulation binders
like
polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, lubricating
agents such as
magnesium stearate, sodium lauryl sulfate and talc are often very useful for
tabletting purposes.
Solid compositions of a similar type may also be employed as fillers in
gelatin capsules;
preferred materials in this connection also include lactose or milk sugar as
well as high
molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs
are desired
for oral administration, the active ingredient may be combined with various
sweetening or
flavoring agents, coloring matter or dyes, and, if so desired, emulsifying
and/or suspending
agents as well, together with such diluents as water, ethanol, propylene
glycol, glycerin and
various like combinations thereof. In the case of animals, they are
advantageously contained in
an animal feed or drinking water in a concentration of 5-5000 ppm, preferably
25 to 500 ppm.
For parenteral administration (intramuscular, intraperitoneal, subcutaneous
and
intravenous use) a sterile injectable solution of the active ingredient is
usually prepared.
Solutions of a therapeutic compound of the present invention in either sesame
or peanut oil or in
aqueous propylene glycol may be employed. The aqueous solutions should be
suitably adjusted
and buffered, preferably at a pH of greater than 8, if necessary and the
liquid diluent first
rendered isotonic. These aqueous solutions are suitable intravenous injection
purposes. The
oily solutions are suitable for intraarticular, intramuscular and subcutaneous
injection purposes.
The preparation of all these solutions under sterile conditions is readily
accomplished by
standard pharmaceutical techniques well known to those skilled in the art. In
the case of
animals, compounds can be administered intramuscularly or subcutaneously at
dosage levels of
about 0.1 to 50 mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a
single dose or up to 3
divided doses.
The active compounds of the invention may also be formulated in rectal
compositions
such as suppositories or retention enemas, e.~c., containing conventional
suppository bases
such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active
compounds of
the invention are conveniently delivered in the form of a solution or
suspension from a pump
spray container that is squeezed or pumped by the patient or as an aerosol
spray
presentation from a pressurized container or a nebulizer, with the use of a
suitable propellant,
e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon
SUBSTITUTE SHEET (RULE 26)


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dioxide or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be
determined by providing a valve to deliver a metered amount. The pressurized
container or
nebulizer may contain a solution or suspension of the active compound.
Capsules and
cartridges (made, for example, from gelatin) for use in an inhaler or
insuftlator may be
formulated containing a powder mix of a compound of the invention and a
suitable powder
base such as lactose or starch.
For topical ocular administration, direct application to the affected eye may
be employed
in the form of a formulation as eyedrops, aerosol, gels or ointments, or can
be incorporated into
collagen (such as poly-2-hydroxyethylmethacrylate and co-polymers thereof), or
a hydrophilic
polymer shield. The materials can also be applied as a contact lens or via a
local reservoir or as
a subconjunctival formulation.
For intraorbital administration a sterile injectable solution of the active
ingredient is
usually prepared. Solutions of a therapeutic compound of the present invention
in an aqueous
solution or suspension (particle size less than 10 micron) may be employed.
The aqueous
solutions should be suitably adjusted and buffered, preferably at a pH between
5 and 8, if
necessary and the liquid diluent first rendered isotonic. Small amounts of
polymers can be
added to increase viscosity or for sustained release (such as cellulosic
polymers, Dextran,
polyethylene glycol, or alginic acid). These solutions are suitable for
intraorbital injection
purposes. The preparation of all these solutions under sterile conditions is
readily accomplished
by standard pharmaceutical techniques well known to those skilled in the art.
In the case of
animals, compounds can be administered intraorbitally at dosage levels of
about 0.1 to 50
mg/kg/day, advantageously 0.2 to 10 mg/kg/day given in a single dose or up to
3 divided doses.
As with the other routes of administration and corresponding dosage forms
described
herein, dosage forms intended for oral administration are also suitably
formulated to provide
controlled-, sustained-, and/or delayed release of the active ingredient.
Typically, these would
include delayed-release oral tablets, capsules and multiparticulates, as well
as enteric-coated
tablets and capsules which prevent release and adsorption of the active
ingredient in the
stomach of the patient and facilitate enteric delivery distal to the stomach,
i.e., in the intestine.
Other typical oral dosage forms would include sustained-release oral tablets,
capsules, and
multiparticulates which provide systemic delivery of the active ingredient in
a controlled
manner over a prolonged period of time, e.g., a 24-hour period. Where rapid
delivery of the
active ingredient is required or desirable, a controlled-release oral dosage
form may be
prepared in the form of a fast-dissolving tablet, which would also preferably
include highly
soluble salt forms of the active ingredient.
The following Examples illustrate the preparation of the compounds of the
present
invention. Melting points are uncorrected. NMR data are reported in parts per
million (cS) and
SUBSTITUTE SHEET (RULE 26)


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are referenced to the deuterium lock signal from the sample solvent
(deuteriochloroform
unless otherwise specified). Commercial reagents were utilized without further
purification.
THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide.
Chromatography
refers to column chromatography performed using 32-63 mm silica gel and
executed under
nitrogen pressure (flash chromatography) conditions. Room or ambient
temperature refers to
20-25°C. All non-aqueous reactions were run under a nitrogen atmosphere
for convenience
and to maximize yields. Concentration at reduced pressure or in vacuo means
that a rotary
evaporator was used.
Example 1
5-(2-Ethoxy-ethyl)-5-[4-(4-[1,3,4joxadiazol-2-yl-phenoxy)-phenoxyj-pyrimidine-
2,4,6-trione
H
O\ /N O
O~CH3
HN
O O ~ ~ O ~ ~ N~N
A.mixture of 4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenol (0.90 g, 2.5 mmol), 5-
Bromo-
5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione (1.0 g, 3.6 mmol), 1,5,7-
trazabicyclo[4.4.0]dec-5-ene
bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 2.4 g, 6.1 mmol)
and 11.7 mL
of acetonitrile was shaken at 23°C for 24 hours. The mixture was
diluted with 30 mL of 25%
acetic acid in methanol, filtered, and the solids were washed twice with
methanol-acetic acid.
The filtrate was concentrated in vacuo and purified by radial chromatography
(2:1 to 1:1
hexane-ethyl acetate), affording 600 mg of 5-(2-Ethoxy-ethyl)-5-[4-(4-
[1,3,4]oxadiazol-2-yl-
phenoxy)-phenoxy]-pyrimidine-2,4,6-trione as a colorless solid.
'H NMR (CD30D): 8.98 (s, 1H), 8.04 (d, 2H, J = 9.0 Hz), 7.07 (d, 2H, J = 9.5
Hz), 7.04
(d, 2H, J = 9.0 Hz), 6.91 (d, 2H, J = 9.0 Hz), 3.61 (t, 2H, J = 5.5 Hz), 3.42
(q, 2H, J = 7.0 Hz),
2.58 (t, 2H, J = 6.5 Hz), 1.15 (t, 3H, J = 7.5 Hz) ppm. MS (m/z, APCI): 496.3
[M-H]-.
4-(4-[1,3,4]Oxadiazol-2-yl-phenoxy)-phenol
A mixture of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole (1.1 g, 4.1
mmol),
methionine (0.94 g, 4.9 mmol) and methanesulfonic acid (20.5 mL) was heated to
50°C for 1.5
hours. The mixture was poured into ice cold 5M sodium hydroxide solution (60
mL), diluted
with sodium bicarbonate solution (saturated aqueous), and was extracted three
times into
ethyl acetate. The combined organic phases were dried over sodium sulfate
(NazS04),
filtered and concentrated in vacuo, affording 4-(4-[1,3,4]oxadiazol-2-yl-
phenoxy)-phenol as a
colorless solid (0.91 g).
SUBSTITUTE SHEET (RULE 26)


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'H NMR (CD30D): 8.97 (s, 1 H), 8.01 (d, 2H, J = 9.0 Hz), 7.04 (d, 2H, J = 9.0
Hz), 6.97
(d, 2H, J = 9.0 Hz), 6.87 (d, 2H, J = 9.0 Hz) PPM.
2-[4-(4-Methoxy-phenoxy)-phenyl]- 1,3,4]oxadiazole
A mixture of 4-methoxybenzeneboronic acid (1.9 g, 12 mmol), 4-(1,3,4)oxadiazol-
2-yl
phenol (1.0 g, 6.2 mmol), copper(II)acetate (1.1 g, 6.2 mmol), crushed 4-
Angstrom molecular
sieves (0.65 g), triethylamine (4.2 mL) and methylene chloride (22.7 mL) was
stirred under 1
atm of oxygen gas for 48 hours. The mixture was filtered through a pad of
Celite0,
concentrated in vacuo and purified by radial chromatography (2:1 hexane-ethyl
acetate),
affording 1.2 g of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole.
'H NMR (CDCI3): 8.44 (s, 1 H), 8.02 (d, 2H, J = 9.0 Hz), 7.05 (m, 4H), 6.95
(d, 2H, J =
7.0 Hz), 3.85 (s, 3H) ppm. MS (m/z, APCI): 300.2 [M+H]+.
5-Bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-triune
To a mixture of 5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-triune (27.8 g, 139 mmol)
and 1.5
L of water was added 1 M sodium hydroxide solution (140 mL) and bromine (7.2
mL, 22.2 g,
139 mmol) at 0°C. After warming to room temperature, the mixture was
stirred for 48 hours,
filtered, and the solids were washed with water, then ether, then hexanes and
dried in vacuo,
afforidng 23 g of 5-bromo-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-triune.
'H NMR (CDCI3): 8.37 (bs, 2H), 3.53 (t, 2H, J = 7.0 Hz), 3.35 (q, 2H, J = 6.5
Hz), 2.99
(t, 2H, J = 7.0 Hz), 1.05 (t, 3H, J = 6.5 Hz) ppm. MS (m/z, APCI): 468.2
(M+H]+.
5-(2-Ethoxy-ethyl)-pyrimidine-2,4,6-triune
Sodium metal (8.6 g, 0.38 mol) was added to ethanol (375 mL), and the mixture
was
stirred at ambient temperature until homogeneous. Diethyl malonate (60 g, 0.38
mol) was
added, followed by bromoethyl ethyl ether (57.4 g, 0.38 mol). After stirring
at reflux for 3
hours, the mixture was cooled to ambient temperature and concentrated in
vacuo. The
resulting material was added to a mixture of sodium ethoxide and ethanol
(prepared by the
reaction of 17.2 g of sodium metal with 600 mL of methanol). Urea (24 g) was
added, and the
resulting mixture was refluxed for 2.5 hours. After cooling to ambient
temperature, the mixture
was stirred for 12 hours, acidified with 1 M hydrochloric acid solution,
extracted three times
with ethyl acetate, and the combined organic layers were dried over sodium
sulfate (NazS04),
filtered and concentrated in vacuo, affording 5-(2-ethoxy-ethyl)-pyrimidine-
2,4,6-triune as a
colorless solid.
SUBSTITUTE SHEET (RULE 26)


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Example 2
N-(4-{4-(5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-

benzyl)-propionamide
H
O\ /N O
O~CH3
N
O
O
O
NH
O
CH3
Following the procedure outlined for the preparation of Example 1, N-[4-(4-
hydroxy-
phenoxy)-benzyl]-propionamide (0.13 g, 0.47 mmol) was reacted with 5-bromo-5-
(2-ethoxy-
ethyl)-pyrimidine-2,4,6-trione (0.13 g, 0.48 mmol), 1,5,7-
trazabicyclo[4.4.0]dec-5-ene bound to
polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.31 g) and 1.55 mL of
acetonitrile,
affording N-(4-{4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-
yloxy]-phenoxy}-
benzyl)-propionamide (0.060 g) as a colorless solid.
'H NMR (CD30D): 7.25 (d, 2H, J = 8.5 Hz), 6.90 (m, 4H), 6.89 (d, 2H, J = 8.0
Hz),
4.33 (s, 2H), 3.59 (t, 2H, J = 6.0 Hz), 3.42 (q, 2H, J = 7.0 Hz), 2.56 (t, 2H,
J = 6.5 Hz), 2.25
(q,2H, J=7.5 Hz), 1.14 (m, 6H) ppm. MS (m/z, APCI): 468.3 [M-H]-.
N-[4-(4-Hydroxy-phenoxy)-benzyl]-propionamide
A mixture of 4-(4-Aminomethyl-phenoxy)-phenol (0.10 g, 0.47 mmol), MMP-resin
(polystyrene bound N-methylmorpholine-type base, 0.30 g, 1.04 mmol) and 1.9 mL
of
acetonitrile was treated with propionyl chloride (0.086 mL, 1.0 mmol) and
shaken for 24 hours
at room temperature. After filtration of the resin, the filtrate was diluted
with 2 mL of methanol
and was treated with 2 mL of 1 M lithium hydroxide (LiOH) in water. The
mixture was shaken
for 24 hours at room temperature, treated with Amberlite IRP-640 resin until
neutral, filtered
and concentrated in vaeuo, affording N-[4-(4-Hydroxy-phenoxy)-benzyl]-
propionamide. MS
(m/z): 272.2 [M+H]'.
Example 3
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4-{4-(5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-phenoxy}-N-
methvl-benzamide
H
O\ /N O
O~CH3
HN O
o H-CH3
Following the procedure outlined for the preparation of Example 1 4-(4-hydroxy-

phenoxy)-N-methyl-benzamide (0.14 g, 0.58 mmol) was reacted with 5-bromo-5-(2-
ethoxy-
ethyl)-pyrimidine-2,4,6-trione (0.16 g, 0.58 mmol), 1,5,7-
trazabicyclo[4.4.0]dec-5-ene bound to
polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.40 g) and 2.0 mL of
acetonitrile,
affording 4-(4-[5-(2-ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-
phenoxy}-N-
methyl-benzamide (0.040 g) as a colorless solid.
'H NMR (CD30D): 7.79 (d, 2H, J = 9.0 Hz), 7.00 (d, 2H, J = 9.5 Hz), 6.95 (d,
2H, J =
8.5 Hz), 6.90 (d, 2H, J = 9.0 Hz), 3.61 (t, 2H, J = 5.5 Hz), 3.42 (q, 2H, J =
7.5 Hz), 2.91 (s,
3H), 2.57 (t, 2H, J = 5.5Hz), 1.14 (t, 3H, J = 7.0 Hz) ppm. MS (m/z, APCI):
440.2 [M-H]-.
1 4-(4-Hydroxy-phenoxy)-N-methyl-benzamide
To a mixture of 4-(4-Hydroxy-phenoxy)-benzoic acid (0.25 g, 1.09 mmol),
triethylamine (0.15 mL, 1.07 mmol) and tetrahydrofuran (THF) (5.0 mL) at
0°C was added
methylchloroformate (0.084 mL, 0.10 g, 1.1 mmol). After stirring for 15
minutes, excess
methylamine was added via a sparge tube, and stirring was continued for 10
minutes. The
mixture was diluted with water, extracted three times with ethyl acetate, and
the combined
organic phases were dried over Na2S04, filtered and concentrated in vacuo,
affording 1 4-(4-
Hydroxy-phenoxy)-N-methyl-benzamide as a colorless syrup.
'H NMR (CDCI3 ): 7.70 (d, 2H, J = 9.0 Hz), 6.87 (m, 6H), 2.96 (s, 3H) ppm. MS
(m/z,
APCI): 244.2 [M-H]-.
Example 4
5-[4-(4-Aminomethyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-
trione
H
O\ /N O
O~CH3
HN O ~ ~ O ~ ~ NH2
O
Following the procedure outlined for the preparation of Example 1, 4-(4-
aminomethyl-
phenoxy)-phenol (0.70 g, 3.32 mmol) was reacted with 5-bromo-5-(2-ethoxy-
ethyl)-pyrimidine-
SUBSTITUTE SHEET (RULE 26)


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2,4,6-trione (0.95 g, 2.4 mmol), 1,5,7-trazabicyclo[4.4.0]dec-5-ene bound to
polystyrene
crosslinked with 2% DVB (PTBD, Fluka, 2.22 g) and 11 mL of acetonitrile,
affording 5-[4-(4-
aminomethyl-phenoxy)-phenoxy]-5-(2-ethoxy-ethyl)-pyrimidine-2,4,6-trione
(0.180 g) as a
colorless solid after purification by reverse phase HPLC.
'H NMR (CD30D): 7.41 (d, 2H, J = 9.0 Hz), 7.00 (d, 2H, J = 9.0 Hz), 6.95 (d,
2H, J =
8.5 Hz), 6.87 (d, 2H, J = 9.0 Hz), 4.08 (s, 2H), 3.60 (t, 2H, J = 6.5 Hz),
3.42 (q, 2H, J = 7.5
Hz), 2.57 (t, 2H, J = 5.5Hz), 1.14 (t, 3H, J = 7.0 Hz) ppm. MS (m/z, APCI):
414.2 [M+H]+.
Example 5
N-(4-{5-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-yloxy]-pyridin-
2-
yloxy}-benzyl)-acetamide
H
O \ /N O
O~CH3
HN O N
O
HN
~O
CH3
Following the procedure outlined for the preparation of Example 1, N-[4-(5-
hydroxy-
pyridin-2-yloxy)-benzyl]-acetamide (0.25 g, 0.97 mmol) when treated with 5-
bromo-5-(2-
ethoxy-ethyl)-pyrimidine-2,4,6-trione (0.20 g, 0.80 mmol), 1,5,7-
trazabicyclo[4.4.0]dec-5-ene
bound to polystyrene crosslinked with 2% DVB (PTBD, Fluka, 0.77 g) and 4 mL of
acetonitrile,
will afford N-(4-{5-[5-(2-Ethoxy-ethyl)-2,4,6-trioxo-hexahydro-pyrimidin-5-
yloxy]-pyridin-2-
yloxy}-benzyl)-acetamide. Expected MS (m/z, APCI): 455 [M-H]-.
The following compounds were prepared according to the methods of Example 1,
substituting the appropriate phenol (e.g. G-B-Y-A-OH) where appropriate.
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+
NUMBER WEIGHT
o N o 460.491
O~CH3
H
O
O
O
7 0\ /N o ~cH3 460.491 461.1
O
HN
O O \ / O
O N o 441.445 442.1
O~CH3
HN
O
O
H
O ~ N~CH3
OO
g ecH, 452.427 453.0
CO
0
0
0 0 \
N
H Q N~N
~N
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+ '~
NUMBER WEIGHT
~ON3 451.443 452.1
'O
o
N
i O
0 0 \ ~ ~ \
H o ~ N,N
N
11 0\ 'N o ~ H3 413 414.2
0
HN NHZ
O
12 ~0"3 450.455 451.1
0
0
0
0 0 \ ~ ~ \
H
0 N
'N
13 O~N 0 CH 455.472 456.1
~1~' p~ 3 H CH3
HN ~ N--
p
14 ~H3 427.417 428.1
0
0
0
o \ ~ I \
0
H p ~ O
H2N
; o"~ 485.501 484.2 [M-H]-
0
o
o ~o ~ ~ I W
N
H 0
\ J
N
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+Hj+
NUMBER WEIGHT
16 ~0"3 462.482 463.1
0
0
"
i O
0 0 \ I I \
O ~5 O
O ~C"3
17 0' 'N o ~cH~ 441.445 442.1
o
HN N-CH3
o O ~ ~ p ~ ~ o
18 O~N O CH3 455.472 456.2
o-/ ~c
HN N-CH3
p O
O
19 0\ 'N o ~cH3 451.44 452.1
0
NN \ N
0
20 p~N o CHI 451.44 452.2
o~
HN - N\
o p
21 o~N o ~c"3 495.496 496.2
0
HN N~N
O \ / O \
O o N~C"3
I
CH3
22 o N o cH, 449.467 448.2
0
HN _
o O \ / \ / N
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+
NUMBER WEIGHT
23 o N o cH3 466.454 467.1
o-
HN N~N
O O
CH3
24 O N O CHI 465.467 , 466.2
o-
HN - N~O
O ~ / O
O / CH3
25 o N o ~CH3 478.481
O
HN -
O
26 o N O ~ H3 441.445 442.2
o
HN -
0 0 ~ ~ O ~ ~ NH
/ z
O
27 o N o ~CH3 451.443 452.2
0
HN ~N
O o ~ ~ ~ ~ NON
28 O N O ~CH3 450.455 451.2
O
HN -
O O \ ~ O ~ ~ N~NH
2g o ~ o cH~ 481.531 482.2
o-
HN - ~ S
O ~ / O ~ ~ N
CHI
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H~+
NUMBER WEIGHT
30 o~N o cH, 465.51 466.2
o~
HN
p p ~ ~ p
-N
31 0~~ o ~cH, 452.512 453.2
0
HN -
p
32 0~,"~ o ~cH, 466.539 467.2
0
HN -
p ~ ~ f
33 o~b o cH3 469.499 470.2
o--~
HN -
O O \ / O
~CH3
//O
34 O N O ~ H3 451.443 452.1
O
_ _ N
O
35 O N O ~ 464.482 465.2
O-
_ N_N ~
Ii p
36 0~~ o cH3 464.482 465.2
H3C
HN N-N
O
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
I EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+
NUMBER WEIGHT
37 O N O CH3 414.419 413.2 [M-H]'
O
HN
O O \ , O \
OH
38 0~,"~ o ~ H, 480.481 481.1
0
HN ~ ~N
° ° \ ~ °
CH3
3g °~~ o- ~ H3 497.553 498.2
0
HN
p ° \ ~ ° \ / H ° CFI
CH3
40 0_ .b o ~a-t, 497.553 498.3
' 0
I-~
o ° \ / ° \ / N o
H \ "
467.504 468.2
41 O N O ~ s
O I
N I
w
O O ~ ~ O
42 p ~ O ~r~ 483.526 484.2
0
HN ~ I
p ° \ ~ ° \ ~ N CH3
H
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
i
I EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+
NUMBER WEIGHT
43 ° N o q.~ 485.498 486.2
O--/
° ° \ / \ / -~
H
O
44 o~b o ~oH, 495.537 496.2
0
HN
o ° \ ~ ° \ ~ N
H
O
45 o N o cH3 497.553 498.2
o--/
o ° \ / ° \ 1 N°
H 3
Gig
46 o N o CH3 469.499 470.3
o---~ o
N
0 \ / O \ / ~CH
O
47 0~~ o ~ H3 467.504 468.2
0
HN
p ° \ ~ \
48 o~p ° ~oH3 462.466
0
HN - N
o ° \ ~ ° \ ~ \ /N
4g 0 N o cH3 466.454 467.1
CH3
HN .- p1
p ° \ ~ p \ ~ N~11N
SUBSTITUTE SHEET (RULE 26)


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TABLE 1
EXAMPLE STRUCTURE MOLECULAR APCI MS [M+H]+
NUMBER WEIGHT
50 o~p p ~ H3 480.481
HN - N~N
p ~ \ ~ ° \ ~ p
CH3
51 p~b o cH3 450.455
o-J
HN O O \ / O \ / N
52 O N o CH3 464.482 465.1
p--~ CH3
N
p ° \ / ° ~ ~ /~N
53 0 ~ o ~H, 478.509 479.1
CH3 CH
/ N
0 ~ ~ ~ O ~ ~ iN
54 p~~ p CH3 450.455
HN - ~ N
p \ ~ ° \ ~ ~ NH
55 ~~b o o~ H3 p 3 470.486 471.1
-CH
HN b
O ~~~ O ~ ~ O
0
56 p~~ o ~ ~~ 498.54 499.2
o--~
F-N
p \/ \/ p
57 °- ~ o o J~ ~ 496.525 497.1
\ / ° \ / p
0
SUBSTITUTE SHEET (RULE 26)